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  • 1
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    The molecular profile of adult T-cell acute lymphoblastic leukemia: Mutations in RUNX1 and DNMT3A are associated with poor prognosis in T-ALL
    Wiley ; 2013
    In:  Genes, Chromosomes and Cancer Vol. 52, No. 4 ( 2013-04), p. 410-422
    Details
    In: Genes, Chromosomes and Cancer, Wiley, Vol. 52, No. 4 ( 2013-04), p. 410-422
    Type of Medium: Online Resource
    ISSN: 1045-2257
    URL: Issue
    URL: Article
    DOI: 10.1002/gcc.v52.4
    DOI: 10.1002/gcc.22039
    Language: English
    Publisher: Wiley
    Publication Date: 2013
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  • 2
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    In BCR-ABL1 Negative Myeloproliferative Neoplasms the Detection of JAK2exon12, MPLW515, CBL, KITD816V, FIP1L1-PDGFRA Mutations Are Closely Linked to Specific Entities, Whereas the JAK2V617F, TET2, or EZH2 Mutations Demonstrate a Broader Diversity: Patterns From Diagnostic Reports of 18,547 Patients Analyzed
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 458-458
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 458-458
    Abstract: Abstract 458 The first mutation detected in BCR-ABL1 negative myeloproliferative neoplasms (MPN) was JAK2V617F that revolutionized diagnostics of MPN during the last five years. However, although this genetic marker is useful to discriminate MPN from reactive disorders, it is not specific for one entity. In addition, approximately 5% of all polycythemia vera (PV) and 50% of essential thrombocytosis (ET) and primary myelofibrosis (PMF) are not JAK2V617F mutated. In these entities other activating mutations, e.g. MPLW515 mutations or JAK2exon12 mutations, cover additional small proportions of patients without JAK2V617F mutation. To further improve the molecular genetic characterization of MPN research focuses on the identification of novel mutations and, recently, CBL, TET2, and EZH2 genes were identified to be mutated in MPN. We here report on our single centre experience in applying these markers in a daily diagnostic work flow comprizing a total cohort of 18,547 cases with suspected MPN that were investigated between 8/2005 und 8/2010 with individual patient specific combinations of these markers as soon as published. Thus, the most frequently tested marker was JAK2V617F that was applied in 17,027 pts. In 6,622/17,027 (38.9%) a definite diagnosis of MPN could be made or confirmed on the basis of the detection of JAK2V617F mutation. More detailed, the percentage of JAK2V617F positive cases varied depending on the suspected diagnoses: In patients with cytomorphologically confirmed or suspected ET 581/891 (65.2%) were JAK2V617F positive, in PMF: 168/290 (57.9%), in PV: 800/942 (84.9%), in MPN-U: 51/212 (24.0%), in CMML: 38/383 (9.9%), in “MPN” not further specified by the referring physician: 4741/11249 (42.1%), and in those with unexplained leukocytosis/thrombocytosis/splenomegaly or suspected hematologic malignancy: 139/2492 (5.6%). Many of the before mentioned cases were suspected MPN and therefore analyzed for both JAK2V617F and BCR-ABL1. Thus, in 9,924 pts BCR-ABL1 and JAK2V617F testing were performed in parallel. As such, in 541/9,924 (5.5%) analyses BCR-ABL1 positive CML was identified and 3,558 cases were JAK2V617F mutated (35.9%). Only 8 pts were BCR-ABL1/JAK2V617F double positive (0.08%), thus this is a very rare event. In cases with JAK2V617F negative PV in a second step JAK2exon12 mutation was analyzed and 27/147 (18.3%) were tested positive. JAK2V617F negative ET or PMF were analyzed in a second step for MPLW515 mutations. In ET 24/258 (9.3%) and in PMF 14/164 (8.5%) cases were tested positive. JAK2exon12 or MPLW515 were never concomitantly detected with JAK2V617 in our cohort (parallel assessments: n=3,769). PCR for detection of FIP1L1-PDGFRA was performed in 1,086 cases with suspected HES/CEL or unclear eosinophilia but only 26 (2.4%) were tested positive and a CEL could be diagnosed. However, in 36/130 (27.7%) FIP1L1-PDGFRA negative cases a KITD816V mutation was detected and thus a diagnosis of mastocytosis could be established. In addition, confirmation of mastocytosis was achieved in further 326/731 (44.6%) pts with suspected mastocytosis, three of these pts had a JAK2V617F mutation in addition. Further analyses were recently done on selected well characterized cohorts of MPN: CBL mutations were analyzed in 623 cases and tested positive in 54 (8.7%): 26/199 CMML (13.0%), 1/25 PMF, 27/293 MPN-U (9.2%), but never were detected in ET (n=61) or PV (n=45). TET2 sequencing detected mutations in 56/191 (29.3%) of pts analyzed: ET: 6/28 (21.4%), PMF: 4/12 (33.3%), PV: 10/31 (32.3%), CMML: 17/22 (77.3%) cases, MPN-U: 17/86: (19.8%), HES: 1/9 cases, Mastocytosis: 1/3 cases. Thus, TET2 mutations are widely spread in different entities and were frequently associated with other mutations: JAK2V617F: n=16, JAK2exon12: n=1, MPLW515: n=2, CBL: n=5, FIP1L1-PDGFRA: n=1, KITD816V: n=1, and EZH2: n=2. Finally, EZH2 sequence analysis detected mutations in 4/68 (5.9%) cases (1/16 PV, 2/11 PMF, 1/17 MPN-U, 0/20 ET, 0/4 CEL). In conclusion, these data show that the analysis of molecular mutations greatly improved the diagnostic work up of MPN in the last 5 years. The detection of some mutations (JAK2exon12, MPLW515, CBL) are useful to further subclassify MPNs. Others (JAK2V617F, TET2, EZH2) are widely distributed and are helpful for classification and also to discriminate MPN from reactive disorders. The individual power of each marker for prognostication in MPN remains to be defined in future studies. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Eder:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.458.458
    RVK:
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    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 3
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    The Impact of Homozygosity and Size of the 13q Deletion in Patients with CLL
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3892-3892
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3892-3892
    Abstract: Abstract 3892 Background: 13q deletions (del(13q)) are the most frequent abnormalities in CLL and, if present as a sole abnormality, associated with favorable outcome. Since the size of the deletion varies considerably, class I (del(13q) not including the RB1 locus) and class II (del(13q) including the RB1 locus) deletions were defined. Previous data suggested that class II deletions were associated with genomic complexity and an unfavorable clinical course. However, confirmation in a large patient cohort was lacking. Aim: Cytogenetic and molecular genetic characterization of patients with class I and class II deletions and evaluation of the impact on outcome. Patients and Methods: 263 cases with newly diagnosed CLL and del(13q) were analyzed by FISH using probes for RB1, D13S25, D13S319 (13q14), ATM (11q22), TP53 (17p13), SEC63 (6q21) and 12 cen. Data from chromosome banding analyses (CBA) (n=263), IGHV mutation status (n=230) and TP53 mutation status (n=206) were also available. Results: 145/263 patients (55.1%) showed a class I and 118 cases (44.9%) a class II deletion. In 79/263 patients (30%) a homozygous del(13q) was observed. No significant difference in frequency of homozygous deletions was observed between cases with class I vs class II deletions (48/145 (33.1%) vs 31/118 (26.3%)). Abnormalities in addition to del(13q): Based on FISH data 66 cases (25.1%) showed abnormalities in addition to del(13q) (del(6q): 5, del(11q): 28, +12: 27, del(17p): 11). The frequency of additional abnormalities did not differ between patients with class I vs class II deletions (25.5% vs 24.6%). Considering also CBA 101 patients (38.4%) showed additional abnormalities. A complex karyotype defined as 3 or more abnormalities in addition to del(13q) was observed in 34 cases (12.9%) and was more frequent in cases with class II deletion (17.8% vs 9.0%, p=0.042). The mean number of abnormalities per case was significantly higher in patients with class II deletions (1.25 vs 0.7, p=0.002). Patients with homozygous del(13q) less frequently showed additional chromosome abnormalities compared to patients with heterozygous del(13q) (22.8% vs 45.1%, p=0.001). IGHV mutation status: In the total cohort, 156/230 patients (67.8%) showed a mutated and 74 (32.2%) an unmutated IGHV status. No difference with respect to the IGHV mutation status was observed between class I vs class II cases. However, an unmutated IGHV status was more frequent in cases with additional abnormalities detected by FISH or CBA compared to those without (52.6% vs 25.4%, p 〈 0.0001 and 48.3% vs 22.4%, p 〈 0.0001). A mutated IGHV status was more frequent in patients with homozygous as compared to heterozygous del(13q) (81.2% vs 62.1%, p=0.005). TP53 mutation status: TP53 mutations were observed in 15/206 cases (7.3%). The TP53 mutation frequency did not differ between class I vs class II patients (6.9% vs 7.8%). However, TP53 mutations were more frequent in cases with additional abnormalities detected by FISH or CBA as compared to those without (18.8% vs 3.8%, p=0.002 and 13.2% vs 3.8%, p=0.023), in cases with complex karyotype (19.2% vs 5.6%, p=0.027), and in cases with TP53 deletions detected by FISH as compared to those without (70.0% vs 4.1%, p 〈 0.0001). Overall survival and time to treatment: OS at 3 yrs in the total cohort was 94% (median time of follow-up of 3.0 yrs). Only Binet stage B/C was significantly associated with shorter OS (p=0.014; relative risk (RR): 6.56). A trend for shorter OS was observed for additional TP53 mutations and/or deletions, while no difference in OS was observed between class I vs class II and homozygous vs heterozygous deletions. The following parameters were associated with longer TTT: no additional abnormalities present in CBA or FISH (p=0.009; RR: 0.55; p=0.010; RR: 0.54), and a mutated IGHV status (p 〈 0.0001; RR: 0.381). A complex karyotype (p=0.040; RR: 1.80) and ATM deletions (p=0.013; RR: 2.04) were associated with shorter TTT. Conclusions: 1. Neither the size nor homozygosity of del(13q) showed impact on OS or TTT. However, a mutated IGHV status and the absence of additional abnormalities were associated with longer TTT. Patients with an additional del(11q) or a complex karyotype showed shorter TTT. 2. A complex karyotype was significantly associated with class II deletions. 3. CLL with del(13q) can be further subdivided by the RB1 deletion status, additional chromosome abnormalities based on CBA and IGHV mutation status. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Zenger:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Dicker:MLL Munich Leukemia Laboratory: Employment. Jeromin:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3892.3892
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 4
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    Whole-exome sequencing identifies somatic mutations of BCOR in acute myeloid leukemia with normal karyotype
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 23 ( 2011-12-01), p. 6153-6163
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 23 ( 2011-12-01), p. 6153-6163
    Abstract: Among acute myeloid leukemia (AML) patients with a normal karyotype (CN-AML), NPM1 and CEBPA mutations define World Health Organization 2008 provisional entities accounting for approximately 60% of patients, but the remaining 40% are molecularly poorly characterized. Using whole-exome sequencing of one CN-AML patient lacking mutations in NPM1, CEBPA, FLT3-ITD, IDH1, and MLL-PTD, we newly identified a clonal somatic mutation in BCOR (BCL6 corepressor), a gene located on chromosome Xp11.4. Further analyses of 553 AML patients showed that BCOR mutations occurred in 3.8% of unselected CN-AML patients and represented a substantial fraction (17.1%) of CN-AML patients showing the same genotype as the AML index patient subjected to whole-exome sequencing. BCOR somatic mutations were: (1) disruptive events similar to the germline BCOR mutations causing the oculo-facio-cardio-dental genetic syndrome; (2) associated with decreased BCOR mRNA levels, absence of full-length BCOR, and absent or low expression of a truncated BCOR protein; (3) virtually mutually exclusive with NPM1 mutations; and (4) frequently associated with DNMT3A mutations, suggesting cooperativity among these genetic alterations. Finally, BCOR mutations tended to be associated with an inferior outcome in a cohort of 422 CN-AML patients (25.6% vs 56.7% overall survival at 2 years; P = .032). Our results for the first time implicate BCOR in CN-AML pathogenesis.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood-2011-07-365320
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 5
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    Ultra-Deep Next-Generation Sequencing Detects RUNX1 Mutations with Unprecedented Sensitivity and Allows to Monitor Minimal Residual Disease In 116 Samples From MDS and AML Patients
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 1691-1691
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 1691-1691
    Abstract: Abstract 1691 RUNX1 (runt-related transcription factor 1) mutations constitute a disease-defining molecular aberration in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Mechanistically, deregulations occur either through balanced translocations or molecular mutations. Importantly, patient-specific RUNX1 mutations have been proposed to represent clinically useful biomarkers to follow disease progression from MDS to s-AML, as well as to monitor minimal residual disease (MRD) during AML treatment. As such, unbiased methodologies are warranted to provide necessary diagnostic sensitivity and throughput. Here, we investigated 116 samples from 25 patients (18 AML and 7 MDS) using next-generation amplicon deep-sequencing. For a longitudinal analysis starting at diagnosis and following the course of treatment peripheral blood (n=20) or bone marrow specimens (n=96) were obtained between 11/2005 and 6/2010. PCR assays targeting the RUNX1 beta isoform were performed with 60 ng of genomic DNA, obtained from mononuclear cells. In median, 5 time points per patient were analyzed with a median time span of 14 months (range: 5 – 34 months). The median sampling interval was 3.2 months. For each patient, one or more molecular mutations were known from standard testing at diagnosis using a combination of denaturing high-performance liquid chromatography and direct Sanger sequencing. In 166 amplicons covering the full spectrum of RUNX1 mutations we applied the 454 small volume Titanium chemistry assay to perform ultra-deep sequencing of specific PCR products (454 Life Sciences, Branford, CT). In median, 3346 reads per amplicon were generated, thereby allowing a highly sensitive assessment of RUNX1 mutational burden in these patients. As such, at 5% diagnostic sensitivity, 167 reads would cover a certain molecular mutation. At a cut-off of 0.5% sensitivity in median 17 reads were remaining for evaluation. First, we evaluated the concordance of NGS and conventional methods for the samples being taken at initial diagnosis. In all 25 patients deep-sequencing analyses concordantly detected the mutations known from conventional methods, i.e. in total 9 missense mutations, 1 nonsense mutation, 2 in-frame alterations, and 13 frameshift alterations. At initial diagnosis, deep-sequencing detected in AML cases the mutations with a median burden of 44% sequencing reads, whereas in MDS cases in median 35% sequencing reads harbored the mutations, respectively. In 2/25 (8%) cases, deep-sequencing detected additional low-level mutations (0.9% and 3.2%) that were not observed by standard techniques. Secondly, we investigated whether the technique of ultra-deep sequencing would be superior to current routine testing methods during follow-up and in detecting MRD. In 7/25 (28%) patients, an increasing clone size was detectable earlier than by conventional methods. Clone sizes with mutations as low as 0.2% - 7.0% of reads were detectable by NGS up to 9 months earlier during course of disease than by conventional methods. In no case did NGS miss mutations known by conventional methods. Overall, in 12/25 (48%) patients, ultra-deep sequencing revealed additional subclones and enabled the quantitative assessment of their respective clone size. In 6/25 (24%) cases this ultra-deep sequencing approach allowed to then quantitatively monitor the changing composition of parallel subclones per patient during treatment and disease progression. In particular, in two MDS patients dominant clones were proven to disappear during course of the disease and existing low-level or novel clones were emerging at s-AML stage. Similarly, in two AML patients dominant clones were suppressed during chemotherapy. Previously existing low-level mutations, already observed at the stage of initial diagnosis, were then detected at relapse with much greater mutational burden. Finally, in 2/25 cases with mutations concomitantly occurring in the same amplicon deep-sequencing was able to delineate monoallelic or biallelic status of the mutation. In conclusion, RUNX1 mutations are useful biomarkers with clinical utility for the detection of MRD in patients with hematological malignancies. We here demonstrated that amplicon-based NGS is a suitable method to accurately detect and quantify the variety of RUNX1 aberrations with high sensitivity and enables an individualized monitoring of disease progression and treatment efficacy. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.1691.1691
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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  • 6
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    Prognostic Impact of NOTCH1 Mutations in Chronic Lymphocytic Leukemia (CLL): A Study On 538 Patients.
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 2873-2873
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 2873-2873
    Abstract: Abstract 2873 Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. Recurrent activating mutations of NOTCH1 have been reported, including the relevance of NOTCH1 mutations as independent negative prognostic marker (Rossi et al., Blood 2012). Aims: 1. Determine the frequency and prognostic impact of NOTCH1 mutations (NOTCH1 mut) in a large unselected cohort of adult CLL patients. 2. Evaluate the range of mutational burden by amplicon deep-sequencing. Patients and Methods: We investigated 538 patients (189 female, 349 male; median age: 66.1 years, range: 37.8 – 90.5 years) with untreated CLL by FISH and for NOTCH1 mut (Transcript ID ENST00000277541) using next-generation amplicon deep-sequencing (454 Life Sciences, Branford, CT). Additionally, TP53 (n=45 mut/523 screened, 8.6%) and IGHV mutation status were analyzed. IGHV status was unmutated in 39.2% (209/533) and mutated in 60.8% (324/533) cases. Since NOTCH1 mut in CLL are known to be located predominantly within the C-terminal PEST domain (Rossi et al., Blood 2012) we sequenced exons 33–34 (covering codons 2029 to 2556), represented by 7 distinct PCR reactions with a median amplicon length of 345 bp. In median, 608 bidirectional reads (range 140–2,117) were generated per amplicon, thereby allowing a sensitive detection of variants, i.e. at a cut-off value of 5% ∼30 independent reads were sequenced. Results: All patients were investigated by FISH: del(17p) (30/538, 5.6%), del(11q) (57/538, 10.6%), +12 (103/538, 19.1%), del(6q) (8/538, 1.5%), normal karyotype according to FISH (NK) (111/538, 20.6%) and del(13q) as sole abnormality (229/538, 42.6%). In total, 81 NOTCH1 mut were observed in 71/538 (13.2%) patients. The vast majority of mutations (98.8%) were found to be heterozygous, only 1/81 mutation (1.2%) was homozygous. We identified 23 point mutations (6 missense and 17 nonsense; 28.4%) and 58 frame-shift alterations (57 deletions and 1 indel; 71.6%). The most frequently occurring mutation was as previously described p.Pro2514ArgfsX4 (c.7541_7542delCT), which was identified in 51/81 (62.7%) variants. The median mutational burden as assessed by deep-sequencing read counts was 28% of sequence reads carrying the mutation (range: 2% - 69%). Of note, in 54/81 (66.7%) variations the detected mutation load was ≤20% and therefore would be below the detection level of Sanger sequencing. In detail, a mutational burden ≤20% was observed in 32/81 (39.5%) variations and ≤10% in 22/81 (27.2%) mutations. 10/71 (14.1%) NOTCH1 mut patients carried 2 mutations. In 9/10 patients a different mutational load between the 2 NOTCH1 mut was detected, indicating the presence of 2 independent clones or clonal evolution with acquisition of a second mutation in the initially NOTCH1 single mutated clone. Mutations mainly clustered in the C-terminal part, i.e. codons 2,385 to 2,555 of exon 34 where 72/81 (88.8%) alterations were located. Confirming published data, statistical analyses revealed NOTCH1 mut being associated with unmutated (unmut) IGHV status (unmut vs mut: 59/209, 28.2% vs 11/324, 3.4%; P 〈 0.001), TP53 mut (mut vs unmut: 10/45, 22.2% vs 58/478, 12.1%, P=0.064) and +12 as sole cytogenetic aberration (+12 sole vs remainder: 23/64, 35.9% vs 48/472, 10.2%; P 〈 0.001). We did not detect any difference in NOTCH1 mut frequency between cases harboring +12 sole and +12 with other aberrations (+12 sole vs +12: 23/64, 35.9% vs 13/45, 28.9%; P=0.54). In contrast, NOTCH1 mut were rare events in patients with del(13q) (del(13q) vs remainder: 24/296, 8.1% vs 47/240, 19.6%; P 〈 0.001). No associations with other cytogenetic subgroups were detected. Univariable cox regression analyses revealed an adverse prognostic impact for NOTCH1 mut (P=0.056) and IGHV unmut (P 〈 0.001). With respect to patients of the favorable prognostic risk group (IGHV mut, TP53 unmut, n=146), NOTCH1 mut patients (n=9) showed a significantly shorter time to treatment (TTT) than NOTCH1 wild-type cases (n=137) (median TTT n.r. vs. 9.4 years, P=0.042). Conclusion: 1. We present the first deep-sequencing study of NOTCH1 mutations in a large unselected CLL cohort and report an overall frequency of 13.2%. 2. The mutational burden of 66.7% of NOTCH1 mutations in CLL patients was ≤20%. 3. NOTCH1 mutations are an adverse prognostic parameter associated with shorter TTT and represent yet another novel important biomarker in CLL. Disclosures: Weissmann: MLL Munich Leukemia Laboratory: Employment. Roller:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.2873.2873
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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  • 7
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    The Role of Different Genetic Subtypes In CEBPA Mutated AML
    American Society of Hematology ; 2010
    In:  Blood Vol. 116, No. 21 ( 2010-11-19), p. 752-752
    Details
    In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 752-752
    Abstract: Abstract 752 To evaluate the role of CEBPA mutations (CEBPAmut) in the context of other molecular mutations and cytogenetic aberrations we have analyzed 1567 AML cases for CEBPAmut. The patients were selected according to cytogenetics excluding the following karyotypes: t(15;17)/PML-RARA, t(8;21)/AML1-ETO, inv(16)/t(16;16)/CBFB-MYH11, inv(3)/t(3;3)/EVI1, t(6;9)/DEK-CAN and 11(q23)/MLL, and complex aberrations. The cohort was composed of 697 females and 870 males. Age ranges from 16.7 to 88.3 years (y) (median: 71.0 y). CEBPAmut were detected in 126/1567 cases (8.0%). The biologic characteristics of the CEBPAmut patients (age range 16.7 to 87.6 y, median: 64.8 y) were further investigated. Three different CEBPAmut patterns were observed: 1) in 50/126 cases (39.7%) one mutation and one wildtype allele were detected (monoallelic pattern), 2) 61 cases (48.4%) had two different mutations (biallelic pattern), 3) 15 cases (11.9%) had one mutation without detectable wildtype allele due to loss of heterozygosity (LOH). Overall we found 186 different mutations of following types: 1) 108 led to a premature N-terminal stop of the protein (6 due to a nonsense and 102 due to a frameshift mutation), 2) 60 were inframe mutations in the b-ZIP region, 3) 8 were frameshifts in the b-ZIP region and, 4) 2 were frameshifts 3`of the b-ZIP region, and 8 were C-terminal point mutations. Correlation to cytogenetics shows a normal karyotype (NK) in 86 (68.3%) of the 126 CEBPAmut patients whereas in 40 pts (31.7%) at least one cytogenetic aberration was detected (-7: n=7; +8: n=7, 9q-: n=2; 11q-: n=3, other trisomies: n=11; other non recurrent translocations: n=4, all others: n=6). Cytogenetic aberrations were more frequent in the monoallelic group (55%) compared to the biallelic (35%) (p=0.001) and to cases with LOH (10%) (p=0.047). Interestingly in the total cohort of 13 pts with monosomy 7 seven pts (53.8%) were CEBPA mutated (53.8%) and of these 6 were in the monoallelic group. Additional mutations were detected in 48 cases (RUNX1: n=11, NPM1: n=10, FLT3-ITD: n=20, FLT3-TKD: n=3, MLL-PTD: n=5, NRAS: n=9, IDH1: n=2, IDH2: n=7; 15 pts showed 2 and 2 pts 3 of these mutations). Similar to the cytogenetic aberrations the molecular mutations were more frequent in the monoallelic group (61.9%) compared to the biallelic (31.0%) and the LOH group (7.1%) (p=0.001). NPM1 mutations were mutually exclusive of biallelic CEBPAmut. As previously described we also detected a significantly higher expression of CD7 in the CEBPAmut compared to the CEBPAwt group (71.2% vs. 18.9%, p 〈 0.001). Furthermore, CD7 was higher expressed in biallelic cases as compared to the monoallelic ones (86.2% vs. 43.8%, p=0.011). It was similar in the LOH group (71.4%) compared to the biallelic group. There was no influence of cytogenetic aberrations or any additional mutation on EFS and OS. Solely the presence of high FLT3-ITD load ( 〉 0.5 FLT3-ITD/FLT3wt) was correlated with a shorter EFS (EFS at 2 y: 20.3% vs. 44.8%; p=0.020) and OS (OS at 2 y 54% vs 68%, p=0.047) when compared to the combined group of FLT3wt and those with an FLT3-ITD load of 〈 0.5. Regarding the different CEBPA groups the biallelic cases had a slightly better OS compared to monoallelic cases (OS at 2 y: 75.0% vs. 60.8%; n.s.). The 2-year OS in the LOH group was significantly lower (33.8%; p=0.023, compared to the biallelic group; and p=0.043 compared to 69.7% in the combined biallelic + monoallelic group). In addition, the different functional mutation types were analyzed. Out of frame mutations in b-ZIP had no specific impact on survival within the CEBPAmut cohort. N-terminal stop mutations and in frame mutations in b-ZIP were associated with favourable outcome (OS at 2 y: 72.1% vs. 43.9% all others mutations, p=0.007 and 2 y OS at 2 y: 76.3% vs. 46.9%; p=0.043, respectively), whereas all other mutations were extremely unfavourable (OS at 2 y: 0% vs. 70.5% compared to N-terminal and b-ZIP mutations, p 〈 0.001). In summary, 1) the biology and prognostic impact varies depending on distinct CEBPAmut patterns. 2) Cytogenetic and molecular alterations had no prognostic impact with the exception of FLT3-ITD with a mutation load of 〉 0.5 FLT3-ITD/FLT3wt. 3) Our data for the first time demonstrate that CEPBAmut with LOH are associated with an even inferior outcome than monoallelic mutations. In conclusion, these data show that CEBPA should be analyzed in detail in all NPM1wt NK AML and in those with unfavourable but non-complex karyotypes. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Alpermann:MLL Munich Leukemia Laboratory: Employment. Eder:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V116.21.752.752
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2010
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    Sensitive Monitoring of Minimal Residual Disease Status in CEBPA-Mutated Acute Myeloid Leukemia Using Amplicon Deep-Sequencing
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2517-2517
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2517-2517
    Abstract: Abstract 2517 Introduction: CEBPA (CCAAT/enhancer binding protein alpha) encodes a member of the basic region leucine zipper (bZIP) transcription factor family essential for myeloid differentiation. CEBPA mutations occur predominantly in AML with a normal karyotype and CEBPA mutated AML has been included as provisional entity in the WHO classification. Cases with biallelic mutations were reported as being associated with a favorable clinical outcome, thus patients are spared from allogeneic transplantation in first CR. Screening for CEBPA mutations in patients with AML is often performed applying a combination of fragment length analysis, DHPLC and subsequent direct sequencing using Sanger technique (conventional methods). Study Design: Next-generation amplicon deep-sequencing (454 Life Sciences, Branford, CT) is a more sensitive quantitative detection method than Sanger sequencing and thus was used to analyze 144 samples from 29 CEBPA mutated AML patients with a normal karyotype. For a longitudinal analysis starting at diagnosis and following the course of treatment bone marrow (n=134) or peripheral blood (n=10) samples were obtained between 5/2006 and 6/2011. The sequencing assay targeted the complete coding region of CEBPA, covered with 4 amplicons, and was performed using genomic DNA extracted from mononuclear cells. In median, 711 reads per amplicon were generated using the NGS assay, thereby allowing a sensitive quantitative assessment of the CEBPA mutational burden in order to monitoring minimal residual disease (MRD). In median, 4 time points per patient (range: 2–9) were included with a median time span of 9.5 months (range: 1–45 months). The median sampling interval was 2 months (range: 0.3–45 months). Results: First, we evaluated the concordance of mutation detection by comparing data from NGS and conventional methods using the samples at initial diagnosis. In all 29 AML patients NGS concordantly detected the mutations known from conventional methods, i.e. in total 26 frame-shifts, 15 in-frame alterations, 8 missense, and 2 nonsense mutations. Further, at initial diagnosis, deep-sequencing detected the mutations with a median burden of 44% sequencing reads (range 3%–88%) and thus already allowed a quantitative assessment of the mutational load. There was no difference observed for 6 patients with monoallelic vs. 21 cases with biallelic mutations (excluding 2 cases with homozygous alterations). We next investigated the distribution of clones and their underlying kinetics of clone size reduction during subsequent high-dose chemotherapy cycles. Overall, 26/29 cases were evaluable and the clone size was assessed by NGS at the second analysis point during course of disease–in median 63 days from time of diagnosis (range 10–215 days): (i) In 16/26 cases, deep-sequencing was not able anymore to detect the mutations as observed at diagnosis. 14 of these 16 negative cases stayed in complete molecular remission till the end of follow-up (median follow-up 6.5 months, range 1–34.2; 2/14 cases with allogeneic stem cell transplantation). (ii) Interestingly, in 4/26 cases residual disease with clones ranging from 8%–50% was indicative of non-response to treatment. In this subgroup 3/4 patients were characterized by resistant disease or early relapse (1 case excluded due to short follow-up). (iii) In the remainder group of 6/26 patients with mutations still detectable in a range of 0.12%–3.7%, complete molecular remission status was achieved at subsequent time points. However, in this group also 3 relapses were observed including 2 cases with allogeneic stem cell transplantation. Of note, in 3/6 cases from the latter group, NGS had outperformed conventional methods and was able to still detect residual clones enabling a superior monitoring of therapy response. In all cases with biallelic mutations both clones responded in parallel with similar kinetics. Moreover, 5 patients were investigated following relapse of AML or non-response to therapy. In all 5/5 analyses including 2 monoallelic and 3 biallelic alterations the same mutations as harbored at initial diagnosis remained detectable. Conclusion:CEBPA mutations provide increasing clinical utility for the detection of MRD. We here demonstrated that deep-sequencing is a suitable unbiased and robust method to accurately detect and quantify CEBPA aberrations enabling an individualized monitoring of disease status and treatment efficacy. Disclosures: Kohlmann: MLL Munich Leukemia Laboratory: Employment; Roche Diagnostics: Honoraria. Grossmann:MLL Munich Leukemia Laboratory: Employment. Fasan:MLL Munich Leukemia Laboratory: Employment. Stopp:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Schindela:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2517.2517
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 9
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    Development and Validation of a Real Time Quantification Assay to Detect and Monitor BRAFV600E-Mutations in Hairy Cell Leukemia,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3674-3674
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    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3674-3674
    Abstract: Abstract 3674 Introduction: So far, the diagnosis of hairy cell leukemia (HCL) was based on cytomorphology, immunophenotyping and histology. Monitoring of the disease during therapy is most sensitively performed by immunophenotyping. The genetics underlying HCL was unclear until very recently, when a BRAF V600E mutation was described to occur in all patients (48/48) with HCL (Tiacci et al., NEJM: 364, 2305–15, 2011). Aim: The aim of this study was to establish and evaluate a reliable genetic test to detect and monitor BRAFV 600E mutations with high specificity and sensitivity. Methods: After testing different variants of DNA or RNA based direct sequencing and melting curve assays we decided for an mRNA-based reverse transcription real time quantification (RQ-PCR) assay that yielded the best sensitivity and specificity. This assay includes a BRAF V600E mutation-specific primer and an additional mismatch nucleotide that further enhances the specific detection of mutated transcripts. The mutated transcripts were normalized against BRAF wildtype (BRAF wt) transcripts. Values are given in %BRAF V600E/BRAF wt. In total, 259 samples were analysed with this assay. First, the specificity of the assay was analysed in 96 samples with a “non-HCL” diagnosis (AML n=9, MDS n=7, MPN n=13, CML n=4, CML in MMR n=10, CMML n=4, CEL n=2, T-ALL n=1, B-ALL n=2, B-NHL n=35, CLL n=2, non-malignant diseases n=7). These samples were used to establish the non-specific background of the assay that can be caused by the normal wild type allele. Subsequently, 124 patients with a proven diagnosis of HCL were analysed (31 females/93 males median age: 59.6 yrs, range 24.3–88.4 yrs). In addition, 16 patients with HCL-variant were analyzed. In 19 of the HCL cases additional follow-up samples were investigated (range, 1–4 samples per patient, total number n=25). Results: Limited dilution series of DNA of 2 cases with highly infiltrated HCL in DNA of a normal control revealed a sensitivity of this assay of 1/10e4-1/10e5. Unspecific %BRAF V600E/BRAF wt values of “non-HCL” controls were very low (median: 0.003, range: 0.000–0.030, SD: 0.005). In the 16 cases with HCL-variant the %BRAF V600E/BRAF wt values were in the same range as in the “non-HCL” controls (median: 0.006, range: 0.000–0.012, SD: 0.004). Based on these results the cut-off level was defined as 0.018 %BRAF V600E/BRAF wt (3xSD over the median). 117/124 cases with proven HCL (94.4%) had a %BRAF V600E/BRAF wt expression that was above the cut-off as defined by normal controls (median: 16.9, range 0.077–280.3). There was a highly significant correlation between the BRAF expression and the percentage of HCL cells as determined by immunophenotyping (r=0.741, p=0.001). The remaining 7/124 (5.6%) HCL patients had %BRAF V600E/BRAF wt values in the range of normal controls and thus are regarded as not carrying the typical BRAF V600E. Deep sequencing using the 454 technology did not reveal any rare BRAF mutations even not at a low levels in any of these 7 cases (median coverage: 427 reads, range: 199–823 reads). In the 19 BRAF V600E-positive patients with follow-up samples an up to 4 log reduction of the %BRAF V600E/BRAF wt was observed during therapy. Comparison of this log reduction with the log reduction as determined by immunophenotyping again revealed a close correlation (r=0.892, p 〈 0.001). In 5 samples values in remission were in the range of negative controls. In one case a relapse was predictable one month before cytomorphologic relapse appeared by an increasing %BRAF V600E/BRAF wt level, paralleling with an increasing percentage of HCL cell as determined by immunophenotyping. Conclusion: 1) BRAF V600E is a new marker that is useful for diagnosis of HCL. 2) This new assay can detect HCL in 〉 94% of cases and BRAF V600E mutations with a specificity of 100%. 3) Given the high sensitivity of 1/10e4-1/10e5 it serves a valuable tool for minimal residual disease detection in HCL. Disclosures: Schnittger: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Wendland:MLL Munich Leukemia Laboratory: Employment. Ulke:MLL Munich Leukemia Laboratory: Employment. Grossmann:MLL Munich Leukemia Laboratory: Employment. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3674.3674
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
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  • 10
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    The Type of Genetic Abnormalities Causing Loss of 5q Varies Between MDS and AML and Is Associated with Worse Prognosis in MDS
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 697-697
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    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 697-697
    Abstract: Abstract 697 Background: Deletions of the long arm of chromosome 5 are frequent abnormalities in MDS and AML. Their size varies considerably. Two commonly deleted regions (CDR) have been described on 5q: a distal CDR deleted in the 5q- syndrome and a proximal region lost in higher-risk MDS and AML. However, the majority of MDS and AML patients with del(5q) show large deletions encompassing both CDRs. Recently, Jerez et al. (JCO 2012) reported on commonly retained regions (CRRs) using SNP arrays and observed that deletions involving the centromeric and telomeric extremes of 5q are associated with a more aggressive clinical course. From a cytogenetic view loss of 5q either occurs due to interstitial deletions, unbalanced translocations or monosomy 5. While in interstitial deletions the telomeric region of 5q is retained, this region is lost in cases with unbalanced 5q translocations and monosomy 5. Aim: Analyze whether the type of 5q loss (interstitial deletion vs unbalanced translocation/ monosomy) is associated with other biological markers and prognosis in AML and MDS. Patients and Methods: In total, 1,200 patients (pts) with loss of 5q were studied including 627 AML pts (de novo: 454, s-AML: 101, t-AML: 72) and 573 MDS pts (de novo: 511, t-MDS: 62) with a median age of 71.7 yrs (range: 30–90) and 73.2 yrs (range: 34–93). Interphase FISH had been performed in all pts with a probe for EGR1 (5q31) and all showed a heterozygous EGR1 deletion. Further, all cases had been studied by chromosome banding analysis and in addition by 24-color FISH whenever necessary to resolve complex karyotypes. Data on TP53 mutation status was available in 263 pts (AML: 152, MDS: 111). Results: Type of 5q loss: AML and MDS cases were separated into 2 groups according to type of 5q loss: 1) interstitial 5q deletion (idel5q): AML: 341/627 (54.4%), MDS: 385/573 (67.2%), and 2) 5q loss due to an unbalanced translocation (ut5q): AML: 286/627 (45.6%), MDS: 188/573 (32.8%). Cases with complete loss of chromosome 5 (AML: 12, MDS: 1) were assigned to the second group. 530/627 (84.5%) AML pts and 303/573 (52.9%) MDS pts with 5q loss showed a complex karyotype (defined as 4 or more abnormalities). Further, in 345 AML (55.0%) and 233 MDS (40.7%) cases clonal evolution was evident as subclones with additional aberrations were detected. Impact of 5q loss in MDS: In MDS clonal evolution and complex karyotypes were more frequent in pts with ut5q as compared to idel5q (109/188 (58.0%) vs 124/385 (32.2%), p 〈 0.0001; 179/188 (95.2%) vs 124/385 (32.2%), p 〈 0.0001). In MDS TP53mut was more frequent in ut5q than in idel5q (8/10 (80%) vs 25/101 (24.8%), p=0.001), in pts with clonal evolution (9/14 (64.3%) vs 24/97 (24.7%), p=0.005) and in pts with complex karyotype (13/15 (86.7%) vs 20/96 (20.8%) p 〈 0.0001). Further, median OS was shorter in pts with ut5q as compared to pts with idel5q (15.3 months (mo) vs not reached, p 〈 0.0001). Impact of 5q loss in AML: Similar to MDS, in AML complex karyotypes were more frequent in pts with ut5q as compared to pts with idel5q (274/286 (95.8%) vs 256/341 (75.1%) p 〈 0.0001). However, in contrast to MDS no association between ut5q and clonal evolution was observed in AML. Moreover, also in contrast to MDS no association between TP53mut and type of 5q loss was observed in AML (TP53mut 59/67 (88.1%) in ut5q pts and 66/85 (77.6%) in idel5q pts). In AML, median OS was comparable in pts with ut5q and pts with idel5q (5.9 mo vs 5.8 mo). However, complex karyotype and the presence of TP53mut were associated with shorter OS in AML (5.5 mo vs 14.0 mo, p=0.32 and 4.8 mo vs 25.1 mo, p 〈 0.0001). In multivariable Cox regression analysis of AML pts including the parameters significant in univariable analyses (complex karyotype, TP53mut, age and WBC count) only TP53mut (HR: 3.28, p=0.011) and WBC count (HR: 1.15 per 10 G/L, p=0.044) were independently associated with shorter OS. Conclusions: 1. Loss of 5q due to unbalanced translocations encompassing the telomeric 5q region is more frequent in AML (45.6%) than in MDS (32.8%) and in both entities associated with a complex karyotype. MDS patients with unbalanced 5q translocations show a shorter survival as compared to patients with interstitial 5q deletions. This data suggests that in MDS unbalanced 5q translocations reflect chromosomal instability which most probably is associated with progression to AML and adverse prognosis. 2. In AML with loss of 5q the presence of TP53 mutations is the strongest adverse prognostic factor. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Equity Ownership. Grossmann:MLL Munich Leukemia Laboratory: Employment. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Kern:MLL Munich Leukemia Laboratory: Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.697.697
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
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