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  • 1
    Online Resource
    Online Resource
    Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation
    Elsevier BV ; 2018
    In:  Hematology, Transfusion and Cell Therapy Vol. 40, No. 2 ( 2018-04), p. 120-131
    Details
    In: Hematology, Transfusion and Cell Therapy, Elsevier BV, Vol. 40, No. 2 ( 2018-04), p. 120-131
    Type of Medium: Online Resource
    ISSN: 2531-1379
    URL: Article
    DOI: 10.1016/j.htct.2017.12.003
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2018
    detail.hit.zdb_id: 2945333-1
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  • 2
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    Erratum on “Philadelphia-negative myeloproliferative neoplasms as disorders marked by cytokine modulation”
    Elsevier BV ; 2021
    In:  Hematology, Transfusion and Cell Therapy Vol. 43, No. 1 ( 2021-01), p. 117-
    Details
    In: Hematology, Transfusion and Cell Therapy, Elsevier BV, Vol. 43, No. 1 ( 2021-01), p. 117-
    Type of Medium: Online Resource
    ISSN: 2531-1379
    URL: Article
    DOI: 10.1016/j.htct.2020.11.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2945333-1
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  • 3
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    High Expression of Human Leukocyte Formin Protein in T Non-Hodgkin’s Lymphomas and in CD19− Cell Population of Normal Tonsils.
    American Society of Hematology ; 2005
    In:  Blood Vol. 106, No. 11 ( 2005-11-16), p. 4662-4662
    Details
    In: Blood, American Society of Hematology, Vol. 106, No. 11 ( 2005-11-16), p. 4662-4662
    Abstract: We recently described a new gene, denominated human leukocyte formin (hlf), which was overexpressed in lymphoid malignancies and cancer cell lines. In contrast, a low expression of the hlf protein was observed in lymph node and peripheral blood leukocytes in normal tissues. Interestingly, the hlf protein associates with Akt, a protein kinase of an important pathway for cell survival. In order to better characterize the expression of the hlf protein we performed Western blotting in the lymphocytes isolated from 4 tonsils from adult patients obtained during routine tonsillectomy, at the Department of Hematology, Clinic Hospital, Barcelona. Results demonstrated that the CD19− cell population of the tonsil displayed a higher expression of this protein when compared with CD19+ cells. In addition, CD19+ cells were separated into two subpopulations: CD27+ (memory cells) and CD27− (naïve cells), and the CD19+/CD27+ cell presented a higher expression when compared with naïve B cells. Furthermore, we performed Western blotting analysis in frozen biopsies of non-Hodgkin’s lymphoma (NHL) patients obtained from the Department of Pathology, Purpan Hospital (Toulouse, France). The lymph node biopsies were performed at the time of clinical diagnosis and the initial diagnosis was confirmed by immunohistochemical analysis and classified according to REAL classification. Fifty-four patients were studied with ages ranging between 28 and 93 years (median 57 years). The histologic types were: 22 follicular NHL, 15 diffuse large B-cell NHL, 17 T cell NHL (non-otherwise specified). Five reactive lymph nodes were also studied. The expression of the hlf protein was detected in all lymphoma samples studied and also in the 5 reactive lymph nodes. The hlf expression, however, was higher in T cell NHL when compared with the others NHL and reactive lymph nodes (T cell NHL vs reactive lymph node, p=0.002; T cell NHL vs follicular NHL, p=0.0001; T cell NHL vs diffuse large B-cell, p=0.012; Mann Whitney test). The hlf protein may be involved in the anti-apoptosis mechanisms, as it is expressed in all types of lymphoproliferative samples and it is associated with Akt, a pathway that is constitutively activated in some hematologic malignancies. Indeed, the ortholog protein described in mice, presents a role in the protection of the cells from apoptosis, but the pathway is unknown. This report provides a more detailed description of the expression of hlf protein in normal lymphocytes and supports the hypothesis that the hlf protein has a role in the cancer molecular pathology of hematologic malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V106.11.4662.4662
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2005
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
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    FMNL1 Is Involved in Immune Response and Hematopoietic Differentiation in MDS
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 1735-1735
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 1735-1735
    Abstract: Abstract 1735 One of the models of the pathophysiology of myelodysplastic syndromes (MDS) suggests that the transformation of hematopoietic cells induces an autoimmune response of T cells with bone marrow (BM) becoming the target organ. Evidence has shown that T-cell mediated marrow suppression is the cause of cytopenia in approximately 20–30% of MDS patients. Higher frequencies of cytotoxic CD8+ cells has been shown in low-risk MDS, as compared to high-risk MDS and these cells mediate the cytotoxicity of BM precursors. On the other hand, the suppressed immune response observed in high-risk MDS results from increased numbers of regulatory T (Treg) cells. FMNL1 belongs to a conserved family of formin-related proteins, indispensable for many fundamental actin-dependent processes, including migration, morphogenesis and cytokinesis. FMNL1 is restrictedly expressed in lymphoid hematopoietic-lineage-derived cells and overexpressed in malignant hematopoeitic cells. Depletion of FMNL1 in cytotoxic lymphocytes was recently reported to abrogate cell-mediated killing. The aim of this work was to study the role of FMNL1 in the immune system of MDS. For this, we characterized FMNL1 expression in peripheral blood CD3+ cells of patients with MDS and normal donor and we evaluated the CD4: CD8 T-cell ratios and molecular markers for Treg cells. We also assessed FMNL1 expression in MDS and normal BM cells, and during hematopoietic cell differentiation, using cell line models. A total of eighty patients with a diagnosis of MDS, receiving no treatment, and forty-seven samples from normal donors were included in the study, which was approved by the National Ethical Committee Board. FMNL1 expression levels were determined by quantitative PCR (q-PCR) or Western blotting in cell lines, CD3+ cells (obtained by Ficoll-Hypaque followed by magnetic selection), or total BM cells. CD3+ cell counts and CD4: CD8 T-cell ratios were determined by flow cytometry. Q-PCR was performed to determine IL-10, TGFB1, and CTLA4 expression in CD3+ cells. Megakaryocytic differentiation was obtained by treating K562 with 20nM of PMA for 4 days. For granulocytic differentiation, NB4 was treated with 10−6 M of ATRA for 4 days. FMNL1 expression was significantly higher in CD3+ cells of the low-risk MDS group (according to FAB, WHO and IPSS classification), compared to normal donors (P 〈 0.03), with no change in CD3+ cell absolute number between these groups. CD4: CD8 T-cell ratios were significantly higher in high-risk MDS, compared to the normal donor group (P 〈 0.03). IL-10 expression levels were significantly higher in the high-risk group, when compared to both low-risk and normal donor groups (P 〈 0.02); TGFB1 and CTLA4 showed no differences. Regarding FMNL1 expression in BM samples, there was a significantly lower expression in MDS, compared with normal donor cells (P =0.04), especially in the high risk group (P =0.02). Using cell line models for hematopoietic differentiation, a fifteen-fold increase and a five-fold increase on FMNL1 expression were observed during megakaryocytic (P =0.002) and granulocytic (P =0.05) differentiation, respectively. Western blot analysis corroborated these findings. The higher expression of FMNL1 in low-risk MDS CD3+ lymphocytes may be related to clonal or oligo-clonal T cell activation, since FMNL1 is important for the cytotoxic function of these cells, which are known to contribute to peripheral blood cytopenia. Indeed, it has already been showed that activation of CD3+ peripheral cells resulted in increased FMNL1 expression. The rise in IL10 transcripts in the CD3+ cells of the high-risk group may be reflecting the increase in Treg, which could be involved in the CD4: CD8 imbalance observed in this group. The lower FMNL1 expression in MDS BM, characterized by disturbed differentiation, could reflect the role of this protein in cell differentiation, as indicated by our cell line studies. Taken together, these results suggest that FMNL1 may be involved in hematopoietic differentiation and in the immune response in MDS. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.1735.1735
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
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    SF3B1, a Splicing Factor Gene, Is Infrequently Mutated in Rare Bone Marrow Failure Diseases but Still Associated with Ring Sideroblast Phenotype
    American Society of Hematology ; 2012
    In:  Blood Vol. 120, No. 21 ( 2012-11-16), p. 3485-3485
    Details
    In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 3485-3485
    Abstract: Abstract 3485 Bone marrow failure syndromes (BMFS) are clonal diseases characterized by inefficient hematopoiesis leading to cytopenias. The clinical and biological heterogeneity often complicates therapy. A number of biological/genetic causes determine the pathogenesis of BMFS (immunological factors, cytokine, telomeres length, T-cell repertoire, epigenetic, apoptotic dysregulation, and chromosomal instability). Whole exome/genome sequencing identified novel mutations in myeloid disorders. SF3B1, a splicing factor gene is mutated primarily in myelodysplastic syndromes (MDS) with ring sideroblasts (RS). SF3B1 mutations brought to light the potential role of spliceosomes in MDS. Although, infrequent in other myeloid malignancies, SF3B1 mutations are relatively frequent in Fludarabine-resistant chronic lymphocytic leukemia (CLL) patients (pts). We previously reported 2 cases: myelofibrosis and paroxysmal nocturnal hemoglobinuria (PNH) with SF3B1 mutations and concomitant RS. To investigate the potential role of SF3B1 in the pathogenesis of rare BMFS, we screened a cohort of BMFS and other rare diseases (N=107): PNH, n=25, aplastic anemia (AA, n=17), T-large granular lymphocytic leukemia (T-LGL, n=17), pure red cell aplasia (PRCA, n=16), and mast cell disease (MCD, n=32) for SF3B1 mutations (exons 13–16) by Sanger sequencing. We identified SF3B1 mutations in 4 pts (MCD; n=2, A711D & K666T; PNH; n=1; K666Q; PRCA, n=1; K666N). Clinical history of the mutated cases showed that the 2 MCD pts fulfilled the criteria for cutaneous and indolent MCD. In the cutaneous MCD pt, skin biopsy revealed typical urticaria pigmentosa highlighting a dermal inflammation with increased MC. No infiltration of MC was found in the BM and no dysplasia was noted, except for RS (6%). In the 2nd pt, the BM was hypocellular with clonal infiltration by MC. No other morphologic features were reported. Mutational analysis of genes implicated in diseases related to MCD, (c-KIT, TET2, IDH1/2, DNMT3A, EZH2, ASXL1, and CBL) showed a wild type configuration in both cases. The close association of MCD with chronic myelomonocytic leukemia (CMML) might explain SF3B1 mutations in the MCD pt as mutations in SF3B1 were reported in 6% of CMML. SF3B1 was also mutated in a pt with 10-year history of hemolytic PNH. BM pathology showed erythroid hyperplasia, no dysplasia, and increased RS (17%) in the BM. Perforin staining showed 〈 0.1% positivity. Cytogenetic analysis showed a normal karyotype. No antecedent BM failure signs were found. The PNH clone was almost completely negative. Single-nucleotide polymorphism array showed the presence of a deletion of the X-chromosome in the PNH cell fraction (O'Keefe CL, Leukemia, 2011). Molecular screening detected absence of JAK2 which has been recently described to be harbored by pts with PNH and a deletion of Xp22.2 (Sugimori C, Blood Cell Cancer, 2012). PIG-A was not mutated. This case also underlines the association of SF3B1 and RS. In addition, SF3B1 could represent a second mutational event leading to PNH expansion in this case. Ultimately, we found SF3B1 mutated in a pt with acquired/PRCA. BM examination showed 50–60% cellularity, absence of erythroid precursors, and no overt sign of dysplasia. FISH analysis using MDS probes for chromosomes 5, 7, 8, and 20 was normal. The pt had increased platelets (470×109/L), macrocytic anemia, and low reticulocytes. No RS was detected in the BM. It is possible that a lymphoproliferative process might be the cause for the presence of SF3B1 mutation. In conclusion SF3B1 is infrequently mutated in rare BMFS. The presence of SF3B1 mutations in cases with no RS might suggest underlying processes not associated with RS, like a lymphoproliferative process. Technical issues in the preparation of BM biopsy samples may also result in undue leaching of iron leading to false negativity reads after Prussian blue staining. It is also possible that sensitive techniques (transmission electron microscopy) may help detecting iron deposits in these cases. The hypocellularity of the BM and paucity of erythroid precursors typically seen in pts with BMF particularly in PRCA, may hamper accurate detection of RS. SF3B1 has been shown to predict better overall survival in pts with MDS and RS. All the mutated pts discussed in this abstract are still alive. The long-term follow up will clarify whether those pts will acquire additional mutational events or changes in their genetic content. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V120.21.3485.3485
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2012
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 6
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    Pharmacological IRS1/2 Inhibition Reduces Cell Viability in BCR-ABL1 Positive Cells
    American Society of Hematology ; 2015
    In:  Blood Vol. 126, No. 23 ( 2015-12-03), p. 2772-2772
    Details
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2772-2772
    Abstract: Introduction: Chronic myeloid leukemia (CML) is a hematological malignancy associated with the BCR-ABL1 fusion gene, which drives the proliferative disease phenotype by activating multiple signaling pathways. Most CML cases are successfully treated with tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1. However, in some cases, drug resistance limits TKIs efficacy, and the identification of other crucial proteins in the BCR-ABL1 signaling pathways may contribute to optimize anti-CML approaches. IRS1 mRNA expression has been previously identified as positively correlated with overall survival in BCR-ABL1-positive adult acute lymphoblastic leukemia. In K562 cells, IRS1 has been identified as a binding partner of BCR-ABL1 protein and was capable of activating PI3K/Akt/mTOR and MAPK pathways. Recently, a pharmacological IRS1/2 inhibitor (NT157) has been developed and has shown promising results in preclinical studies on solid tumors. We herein aimed to investigate IRS1 and IRS2 expression and the effects of IRS1/2 inhibition on cell proliferation, apoptosis and clonogenicity in BCR-ABL1 positive and normal hematopoietic cells. Materials and Methods: Total bone marrow cells from healthy donors (n=11) and CML patients at the time of diagnosis (n=24) were submitted to gene expression analysis by quantitative PCR with specific primers for IRS1, IRS2 and β-actin. All subjects provided informed written consent and the study was approved by the ethics committee of the Institution. K562 cells were submitted to IRS1/2 pharmacological inhibition using NT157 (0.2, 0.4, 0.8, 1.6, 3.2 and/or 6.4 µM) for 24, 48 and 72 hours and were evaluated for cell viability (MTT assay), proliferation (Ki-67), apoptosis (Annexin V/PI), and protein expression/activation (Western blot). Alternatively, cells were submitted to IRS1 and IRS2 gene silencing using specific shRNA lentiviral delivery, and submitted to functional studies. NT157 effects were analyzed by in vitro hematopoietic colony formation of bone marrow cells from two patients with CML at diagnosis, and of normal cord blood cells from one individual. Cells were seeded at 4.5x104 per well in a culture system for 14 days. Statistical analyses were performed by Student's t-test or Mann-Whitney test, as appropriate. Results: IRS1 and IRS2 mRNA expression was similar between normal donors and CML samples (p ≥.05). NT157 treatment reduced K562 cell viability in a time and dose-dependent manner; using a nonlinear regression analysis, IC50 for cytotoxicity was 9.8, 0.6 and 0.68 µM for 24, 48 and 72 hours, respectively. NT157 0.8 and 3.2 µM reduced cell viability in 14% and 19% at 24 hours, 50% and 61% at 48 hours and in 59% and 68% at 72 hours of treatment (all p 〈 .05). After 48 hours of NT157 exposure, Ki-67 staining revealed a decrease in cell proliferation by 10% at 0.8 µM, 40% at 1.6 µM, and 75% at 3.2 µM. Pharmacological IRS1/2 inhibition significantly induced apoptosis as noted by increased cleaved caspase 3 and 9 by Western blotting analysis, and AnnexinV/PI staining. The percentage of apoptotic (AnnexinV+) cells for control, NT157 0.8 and 3.2 µM at 48 hours of treatment were 15%, 38% and 61%, respectively (p 〈 .05). Upon NT157 0.8, 3.2 and 6.4 µM, colony formation of CML primary cells was inhibited by 7%, 36% and 78% for patient #1, and by 29%, 19% and 62% for patient #2, with a reduction predominance in granulomonocytic colonies for both patients. Interestingly, NT157 treatment did not inhibit colony formation of committed normal cord blood cells; the number of colonies for control, NT157 0.8, 3.2 and 6.4 µM were 88, 84, 97, and 92, respectively. Of note, lentiviral-mediated silencing of IRS1, but not of IRS2, significantly decreased K562 cell viability. Conclusion: Although IRS gene expression analysis did not differ between CML patients and normal controls, the functional studies indicate that IRS protein activation status is implicated in the biology of CML cells. NT157 pharmacological IRS1/2 inhibition (i) reduces colony formation in primary CML, but not in normal cells, (ii) decreases cell viability and proliferation, and (iii) increases apoptosis of K562 cells in a time and dose-dependent manner. Since IRS2 lentiviral-mediated silencing did not reduce K562 cell viability, IRS1 inhibition may be the main mechanism by which NT157 exerts its effects on BCR-ABL1 positive cells. NT157 IRS1/2-targeting may optimize the anti-CML approaches. Disclosures No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V126.23.2772.2772
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 7
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    Higher Rates of AML Transformation and Poor Risk Cytogenetics in Patients with Low Average Albumin Levels Confers Poor Prognosis in Myelodysplastic Syndromes,
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 3832-3832
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 3832-3832
    Abstract: Abstract 3832 Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders characterized by reduced hematopoiesis and progression to leukemia. Albumin is a prognostic biomarker in many malignant and non-malignant conditions, including multiple myeloma, chronic inflammation and aging. Recently, one study (Yepez, M, ASH 2010, abst #4001) showed that hypoalbuminemia was an independent prognostic factor in MDS. However, serum albumin levels can vary with time and be influenced by nutrition, age and presence of other comorbidities which are prevalent in MDS. To have an accurate assessment, we took the average serum albumin level of MDS patients over a period of 6 months. We hypothesize low average albumin will confer worse outcomes We conducted a retrospective analysis of 237 MDS patients seen in Cleveland Clinic between 1999 and 2009 (RARS= 30, RCMD=25, RAEB1/2=61, 5q- syndrome= 4, CMML1/2=39, MDS/MPN-U=32, RARS-T=30, RCUD=26). A total of 194 patients were included since average albumin was able to be calculated. The median age is 66 (20–92) years. Median follow-up time is 15 months (0–81 months). Clinical information including age, SNP-A karyotyping results, hemoglobin and serum albumin at time of diagnosis, average serum albumin level over 6 months, absolute neutrophil count, platelet counts, bone marrow blasts, and metaphase cytogenetic results were obtained.Patients were divided based on IPSS into lower and higher risk disease. We analyzed a total of 123 patients in the lower risk and 71 patients in the higher risk group. Further, we subdivided patients into lower albumin level ( 〈 3.5) or higher (3.5 or greater) based on the average albumin over 6 months. The median overall survival (OS) of the cohort is 15 months. Categorical variables were analyzed using Fisher's exact test. The Cox-proportional hazards model was used to assess univariate and multivariate analyses for OS and progression free survival (PFS); factors assessed included age (≥60 vs. 〈 60 years), disease grouping (MDS and MDS/MPN vs sAML), BM blasts (≥5 vs. 〈 5 %), Hgb level (≥10 vs. 〈 10 g/dL), metaphase cytogenetics (MC) risk groups using IPSS criteria (good, intermediate, poor), presence or absence of new SNP lesions and average albumin level. Each variable was retained in the multivariate model regardless of its statistical significance. Only variables with p 〈 .05 in multivariate analysis were considered significant. Similar to the study by Yepez M et al, we also found that serum albumin level at the time of original diagnosis is prognostic in MDS and related disorders. Patients with low albumin levels at diagnosis ( 〈 3.5) have a worse OS compared to those with high albumin levels (6 vs 16 mos, p=.005). However, this was possible with a dichotomized albumin level. More importantly, we also found that the lower average serum albumin level [OS (8 vs 30 mos, p=.0001) and PFS (5 vs 20 mos, p= 〈 .0001)] over 6 months can also be prognostic in MDS but not in MDS/MPN and sAML. Patients with low average albumin have poorer survival compared to patients with high albumin (OS: 6 vs 23 months, p= 〈 .0001; PFS: 5 vs 15 months, p= 〈 .0001). The same statistically significant findings were observed in patients stratified to lower (OS: 9 vs 37 mos, p=.001; PFS: 5 vs 24 mos, p= 〈 .0001) or higher (5 vs 13 mos, p=.03) risk MDS by IPSS. Multivariate analysis showed that low average albumin level is an independent predictor of poor outcomes in MDS (OS: HR=2.12 CI:1.53–2.99, p= 〈 .0001; PFS: HR=1.91 CI:1.31–2.76, p=.0009). Similarly, previously validated poor prognostic factors in MDS remained significant (Age ≥60 [HR:1.87, p=.0003], sAML disease grouping [HR:2.08, p=.0001] , Hgb 〈 10 g/dl [HR:1.42, p=.009], BM blasts [HR:1.44, p=.03] , Poor risk cytogenetics [HR:2.22, p=.004], and presence of new SNP lesions [HR:1.59, p=.0008] . To identify factors that may result in worse outcomes in low average albumin patients, we assessed treatment response differences between patients which were not significant between low and high albumin levels. However AML transformation [(42/92 (45%) vs 111/150 (74%), p.002] and cytogenetics [Poor vs Good/Intermediate (21/43 (49%) vs 55/185 (30%), p=.02)] correlated with lower average albumin levels. In conclusion, low average serum albumin levels are an independent predictor of worse outcomes in MDS. Moreover, these data suggest that low average serum albumin is associated with poor risk karyotype and with progression to AML. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.3832.3832
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    The CALM/AF10 Interactor CATS Is a Substrate of KIS, a Positive Regulator of Cell Cycle Progression in Leukemia Cells
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2549-2549
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2549-2549
    Abstract: Abstract 2549 The CATS protein (also known as FAM64A and RCS1) was first identified as a novel CALM (PICALM) interactor that interacts with and influences the subcellular localization of CALM/AF10, a leukemic fusion protein found in acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL) and in malignant lymphoma. CATS is highly expressed in leukemia, lymphoma and tumor cell lines but not in non-proliferating T-cells or in peripheral blood lymphocytes (PBLs). The protein levels of CATS are cell cycle-dependent, induced by mitogens (e.g. PHA) and correlate with the proliferative state of the cell. Thus, CATS is as a marker for proliferation. Using CATS as a bait in a yeast two-hybrid screen we identified the Kinase Interacting Stathmin (KIS or UHMK1) as a CATS interacting partner. KIS is a serine/threonine kinase that positively regulates cell cycle progression through phosphorylation of p27KIP in leukemia cell lines. The interaction between CATS and KIS was confirmed by GST pull-down, and co-immunopreciptation. KIS interaction region was mapped to CATS N-terminal portion. Searching through the phosphorylation site databases PhosphoSitePlus™ (http://www.phosphosite.org) and Phosida (http://www.phosida.com/) we identified 9 residues within CATS shown to be subject of post-translational modification. Phosphorylation assay with recombinant KIS demonstrated that this kinase efficiently phosphorylated full length CATS and its N-terminal part, but not the C-terminal of the protein. To map the KIS phosphorylation site of CATS, peptides comprising all known phospho-sites of CATS N-terminal (S16, S129, S131, T133 and S135) and mutations of the putative KIS target motif (S129 and S131) were tested for KIS phosphorylation. Thereby, we identified CATS S131 as the unique target site for KIS phosphorylation. Western blot analysis of U2OS cells, which had undergone cell cycle synchronization by a double thymidine block, revealed that KIS fluctuated throughout the cell cycle and counteracted CATS levels. Furthermore, we analyzed KIS protein expression on bone marrow mononuclear cells (MNCs) of MDS and AML patients. We studied 5 healthy donors, 13 MDS patients (7 low-risk [RA/RARS] and 6 high-risk [RAEB/RAEBt] according to FAB classification) and 10 AML patients (7 de novo and 3 secondary). Western blot analysis revealed elevated levels of KIS in MDS and AML compared to the control samples. We used a reporter gene assay in order to determine the influence of KIS on the CATS-mediated transcriptional repression and to elucidate the role of KIS-dependent phosphorylation of CATS at serine 131 in this context. Coexpression of GAL4-DBD-CATS and KIS enhanced the inhibitory function of CATS on transactivation of the GAL4-tk-luciferase reporter. This effect of KIS was observed for both CATS wild type and CATS phospho-defective mutant (CATS S131A) but not when the kinase dead mutant KISK54R was used. Moreover, CATS phosphomimetic clone (CATSS131D) exerted the same transcriptional activity as the CATS wild type. These results demonstrate that KIS enhances the transcriptional repressor activity of CATS, and this effect is independent of CATS phosphorylation at S131 but dependent on the kinase activity of KIS. Finally, we investigated whether CATS would affect the CALM/AF10 function as an aberrant transcription factor. Coexpression of constant amounts of GAL4-DBD-CALM/AF10 and increasing amounts of CATS lead to reduced transactivation capacity of CALM/AF10 in a dose dependent manner. Our results show that CATS not only interacts with but is also a substrate for KIS, suggesting that CATS function might be modulated through phosphorylation events. The identification of the CATS-KIS interaction further supports the hypothesis that CATS plays an important role in the control of cell proliferation. Moreover the elevated levels of KIS in hematological malignances suggest that KIS could regulate CATS activity and/or function in highly proliferating leukemic cells. Thus our results indicate that CATS function might be important to understand the malignant transformation mediated by CALM/AF10. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2549.2549
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
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  • 9
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    Increased Inflammatory Markers and Their Correlations To Clinical Complications In Hemoglobin SC Disease
    American Society of Hematology ; 2013
    In:  Blood Vol. 122, No. 21 ( 2013-11-15), p. 973-973
    Details
    In: Blood, American Society of Hematology, Vol. 122, No. 21 ( 2013-11-15), p. 973-973
    Abstract: Hemoglobin SC (HbSC) disease is the second most prevalent hemoglobinopathy after sickle cell anemia (SCA – homozygous HbSS). Despite its high prevalence, most of the knowledge about the pathophysiology of HbSC is inferred from studies focused primarily on SCA. In general, HbSC is considered a milder form of SCA. Chronic inflammatory activity is clearly seen in SCA, but not much is known about the inflammation present in HbSC. In the present study we aimed to evaluate inflammatory markers in HbSC patients and their associations with clinical and laboratory characteristics of the disease. This was a cross-sectional study performed on a cohort of 56 HbSC patients (mean age of 41 years), 39 SCA patients (mean age of 34 years), and 24 healthy age-matched controls. All of the patients were in steady state, with no history of painful crisis, hospitalization or transfusions during the preceding 3 months. None of the patients were in use of hydroxyurea. We evaluated the inflammatory markers, tumor necrosis factor-alpha (TNF-α) and interleukin 8 (IL8). Levels of inflammatory markers were correlated with hemolysis markers, blood counts, coagulation markers (tissue factor expression [TF], thrombin-antithrombin complex [TAT] , d-dimer [DD]) and endothelial activation marker (soluble thrombomodulin [sTM] ). TNF-α, IL8, TAT, DD and sTM were all measured by ELISA. Leukocyte TF mRNA expression was analyzed by real time quantitative PCR. Statistical analyses were performed by Mann-Whitney’s U test and Spearman’s rank correlation test. HbSC patients presented higher TNF-α levels than those of controls (2.72 vs. 0 pg/mL; P 〈 0.0001), which were similar to the levels seen in SCA patients (2.72 vs. 2.74 pg/mL; P = 1.0). IL8 levels were similar between HbSC patients and controls (2.54 vs. 2.29 pg/mL; P = 0.16) and also similar between HbSC and SCA patients (2.54 vs. 2.82 pg/mL; P = 0.45). In the analyses of the HbSC cohort, IL8 levels presented significant positive correlations with: leukocyte (r=0.4; P=0.02), monocyte (r=0.5; P=0.001), and platelet counts (r=0.6; P=0.0002); and hemolysis markers: indirect bilirubin (r=0.4; P=0.04) and lactate dehydrogenase levels (r=0.4, P=0.04). TNF-α levels presented no significant correlations with laboratory markers. We also evaluated associations between IL8 and TNF-α levels and clinical complications; stroke, pulmonary arterial hypertension, acute thoracic syndrome, retinopathy, osteonecrosis, leg ulcers and autosplenectomy. HbSC patients with osteonecrosis had significantly higher IL8 levels (3.8 vs. 2.4; P=0.01) when compared with patients without this complication. IL8 levels were also higher in patients with autosplenectomy (3.8 vs. 2.0; P=0.0003). Our results indicate that HbSC disease patients present elevation of inflammation markers, similar to alterations seen in SCA. In our cohort, patients with higher peripheral blood counts and a more intense hemolytic activity, such as patients with autoesplenectomy, have higher levels of inflammatory markers. Our data suggest that inflammation may be a factor contributing to the pathophysiology of a very prevalent chronic complication of HbSC disease, osteonecrosis. Studies focusing on the pathophysiology of HbSC disease are lacking, and in view of the high prevalence of this disease we believe it should be the focus of future studies. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V122.21.973.973
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2013
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 10
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    Pathogenesis of MONOSOMY 7 In BONE MARROW FAILURE SYNDROMES
    American Society of Hematology ; 2011
    In:  Blood Vol. 118, No. 21 ( 2011-11-18), p. 2411-2411
    Details
    In: Blood, American Society of Hematology, Vol. 118, No. 21 ( 2011-11-18), p. 2411-2411
    Abstract: Abstract 2411 One of the most serious complications of aplastic anemia (AA) is the clonal evolution to myelodysplastic syndrome (MDS). Monosomy 7 (del[7]) is the most common chromosomal aberration encountered in this setting, but it can also occur in primary MDS along with deletion 7q (del[7q] ). In our whole cohort of AA, we detected del[7] in 24 cases of clonal evolution; however, unlike in MDS no cases of del[7q] were observed. In contrast, in MDS or myelodysplastic/myeloproliferative neoplasms, del[7]/[7q] were present in 12% and 11%, respectively. Based on an initial observation of an index AA case with a mutation of CBL, we speculated that certain molecular events such as point mutations can promote or are at least associated with the evolution of del[7]. Given the distinct distribution of del[7] and del[7q] in primary and secondary MDS (derived from AA), we stipulate that the associated mutational pattern will be distinct. This may be due to different driving mechanisms, such as immune escape or a growth factor-rich milieu in AA. Pursuant to this theory, we performed a screen for CBL, RUNX1, TET2, UTX, EZH2, DNMT3A, ASXL1 and IDH family mutations in patients who developed del[7] after AA (N=24). 14 cases were adults and 10 were pediatric cases. In addition, we analyzed 15 del[7] , 13 del[7q] and 10 UPD[7q] abnormalities in patients with MDS without antecedent AA. We identified 3 CBL (13%), 5 RUNX1 (20%), 1 TET2 and 1 DNMT3A mutation in patients with del[7] after AA; all CBL mutations are observed in adult cases of AA (21%). However, 0, 1, and 2 CBL mutations were found in primary MDS with del[7] , del[7q] and UPD[7q] , respectively. In contrast, RUNX1 mutations were seen in both AA sub-groups (14% and 30% in adults and children, respectively). Also, no differences were seen with regard to the distribution of RUNX1 mutations in either post-AA MDS with del[7] or primary MDS with del[7] , del[7q] and UPD[7q] . Most significantly, ASXL1 was found to be the most frequently mutated gene in the cohort without AA (37%), although no mutations were seen in patients with del[7] after AA. Additionally, UTX and EZH2, both involved in the trimethylation of histone H3 lysine 27, were found to be mutated only in cases of MDS with UPD[7q] and del[7q], but no mutations were seen in primary and AA-derived MDS with del[7] . When studied serially, none of the tested mutations was seen in the initial AA phase, but the mutated clone increased gradually during clonal evolution of del[7]. We also investigated the presence of additional chromosomal abnormalities using single nucleotide polymorphism array (SNP-A)-based karyotyping in the cases with del[7] after AA. In addition to del[7] , 22 gains, 20 losses and 4 regions of somatic uniparental disomy (UPD) were identified. These abnormalities, including microdeletions, were found in 50% and 60% of adult and pediatric cases, respectively. Recurrent lesions were detected on chromosome 6, 8 and 21. A microdeletion on chromosome X involved the tumor-associated gene PHF6 in a male case. In another patient, trisomy 21 was accompanied by a RUNX1 mutation. Regions of UPD included 6p resulted in loss of heterozygosity of MHC class I and 11q was associated with homozygous CBL mutations in 2 cases. In sum, our analysis supports the theory that distinct mechanisms of molecular progression during MDS evolution may be operative in AA and primary MDS. Moreover, del[7], del[7q] and UPD[7q] have distinct molecular profiles with frequent TET2 mutations in del[7q] and UPD[7q]. ASXL1 mutations appear to be most ubiquitous promoting event in MDS with LOH [7/7q] , suggestive of their “type II' nature. In contrast, other mutations such as those in CBL may be selected for e.g., through cytokine-rich milieu and activation of CBL-regulated receptor tyrosine kinases. Disclosures: No relevant conflicts of interest to declare.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V118.21.2411.2411
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2011
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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