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  • 1
    Online Resource
    Online Resource
    Interaction of the developmental regulator SALL1 with UBE2I and SUMO-1
    Elsevier BV ; 2002
    In:  Biochemical and Biophysical Research Communications Vol. 296, No. 4 ( 2002-08), p. 870-876
    Details
    In: Biochemical and Biophysical Research Communications, Elsevier BV, Vol. 296, No. 4 ( 2002-08), p. 870-876
    Type of Medium: Online Resource
    ISSN: 0006-291X
    URL: Article
    DOI: 10.1016/S0006-291X(02)02003-X
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2002
    detail.hit.zdb_id: 1461396-7
    SSG: 12
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  • 2
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    Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia
    Proceedings of the National Academy of Sciences ; 2004
    In:  Proceedings of the National Academy of Sciences Vol. 101, No. 3 ( 2004-01-20), p. 817-822
    Details
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 101, No. 3 ( 2004-01-20), p. 817-822
    Abstract: Creation of fusion genes by balanced chromosomal translocations is one of the hallmarks of acute myeloid leukemia (AML) and is considered one of the key leukemogenic events in this disease. In t(12;13)(p13;q12) AML, ectopic expression of the homeobox gene CDX2 was detected in addition to expression of the ETV6-CDX2 fusion gene, generated by the chromosomal translocation. Here we show in a murine model of t(12;13)(p13;q12) AML that myeloid leukemogenesis is induced by the ectopic expression of CDX2 and not by the ETV6-CDX2 chimeric gene. Mice transplanted with bone marrow cells retrovirally engineered to express Cdx2 rapidly succumbed to fatal and transplantable AML. The transforming capacity of Cdx2 depended on an intact homeodomain and the N-terminal transactivation domain. Transplantation of bone marrow cells expressing ETV6-CDX2 failed to induce leukemia. Furthermore, coexpression of ETV6-CDX2 and Cdx2 in bone marrow cells did not accelerate the course of disease in transplanted mice compared to Cdx2 alone. These data demonstrate that activation of a protooncogene by a balanced chromosomal translocation can be the pivotal leukemogenic event in AML, characterized by the expression of a leukemia-specific fusion gene. Furthermore, these findings link protooncogene activation to myeloid leukemogenesis, an oncogenic mechanism so far associated mainly with lymphoid leukemias and lymphomas.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
    URL: Article
    DOI: 10.1073/pnas.0305555101
    RVK:
    TA 1000
    RVK:
    WA 15000
    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2004
    detail.hit.zdb_id: 209104-5
    detail.hit.zdb_id: 1461794-8
    SSG: 11
    SSG: 12
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  • 3
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    Online Resource
    Towards the In Vivo Identificaton of Leukemogenic Fusion Proteins.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2970-2970
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2970-2970
    Abstract: Currently there are no methods available to identifiy leukemogenic fusion proteins in vivo. All available methods, like Southern blotting, PCR, FISH or Western blotting, require the destruction of the cells that are assayed. A method for the in vivo detection of leukemogenic fusion proteins would be highly desirable because it would open up new approaches to study leukemia and might lead to novel treatment strategies. We have developed a strategy for the in vivo detection of the BCR/ABL fusion protein. BCR/ABL is found in virtually all cases chronic myeloid leukemia (CML) and a large proportion of acute lymphoblastic leukemia (ALL). Animal model have shown that the BCR/ABL fusion protein is required for the induction and maintenance of leukemia. The fact that BCR/ABL fusion protein is crucial for the development of leukemia makes this fusion protein an attractive target for therapy development. Our BCR/ABL detection strategy is based on protein-protein interactions and a proof of principle for the strategy was implemented in the yeast system. Two detection proteins are expressed in the cells: 1) protein A, a Gal4-DNA binding domain/BCR interacting protein fusion protein and 2) protein B, a Gal4-activation domain/ABL interacting protein fusion protein. Only when BCR/ABL is present in the cell, do protein A, protein B, and BCR/ABL form a trimeric complex which activates the transcription of reporter genes under the control of Gal4-upstream activating sequence (UAS). Yeast cells (strain CG1945) transformed with a protein A expressing plasmid (pGBT9-BCR-interactor), a protein B expressing plasmid (pGAD424-ABL1-interactor), and a BCR/ABL expressing plasmid (pES1-BCR/ABL) showed expression of the reporter genes HIS3 and LACZ. The expression of the HIS3 reporter gene was assayed by growth of the yeast cells on medium lacking histidine. The expression of the LACZ gene was verified by a beta-galactosidase filter assay. Yeast cells that were transformed with the pES1 plasmid without the BCR-ABL coding region did not show activation of the reporter genes. Several other negative controls were also negative. Thus the method was able to clearly distinguish between BCR/ABL expressing cells and cells did not express BCR/ABL. We are presently adapting this system for use in mammalian cells. The flexibility of our strategy allows us to freely choose the reporter or effector genes. Therapeutically more useful effector genes are suicide genes, which encode pro-drug converting enzymes (e.g. HSV thymidine kinase), or markers that can easily be assayed (e.g. green fluorescent protein).
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.2970.2970
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    A t(1;9)(q23.3∼q25;q34) affecting the ABL1 gene in a biphenotypic leukemia
    Elsevier BV ; 2004
    In:  Cancer Genetics and Cytogenetics Vol. 152, No. 1 ( 2004-7), p. 81-83
    Details
    In: Cancer Genetics and Cytogenetics, Elsevier BV, Vol. 152, No. 1 ( 2004-7), p. 81-83
    Type of Medium: Online Resource
    ISSN: 0165-4608
    URL: Article
    DOI: 10.1016/j.cancergencyto.2003.10.014
    RVK:
    XA 10000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2004
    detail.hit.zdb_id: 2004205-X
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  • 5
    Online Resource
    Online Resource
    Molecular cytogenetic analysis of a de novo balanced X;autosome translocation: Evidence for predominant inactivation of the derivative X chromosome in a girl with multiple malformations : t(X;15) With Inactivation of der(X)
    Wiley ; 2004
    In:  American Journal of Medical Genetics Part A Vol. 126A, No. 3 ( 2004-04-30), p. 229-236
    Details
    In: American Journal of Medical Genetics Part A, Wiley, Vol. 126A, No. 3 ( 2004-04-30), p. 229-236
    Type of Medium: Online Resource
    ISSN: 1552-4825
    URL: Issue
    URL: Article
    DOI: 10.1002/ajmg.a.v126a:3
    DOI: 10.1002/ajmg.a.20584
    Language: English
    Publisher: Wiley
    Publication Date: 2004
    detail.hit.zdb_id: 1493479-6
    SSG: 12
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  • 6
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    Identification of an ETV6-ABL2 fusion transcript in combination with an ETV6 point mutation in a T-cell acute lymphoblastic leukaemia cell line : ABL2 and ETV6 in a T-ALL with Lineage Switch
    Wiley ; 2002
    In:  British Journal of Haematology Vol. 119, No. 2 ( 2002-11), p. 454-458
    Details
    In: British Journal of Haematology, Wiley, Vol. 119, No. 2 ( 2002-11), p. 454-458
    Type of Medium: Online Resource
    ISSN: 0007-1048
    URL: Article
    DOI: 10.1046/j.1365-2141.2002.03850.x
    RVK:
    XA 34100
    Language: English
    Publisher: Wiley
    Publication Date: 2002
    detail.hit.zdb_id: 1475751-5
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  • 7
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    Perturbed Endocytosis by CALM-Containing Fusion Proteins: A Leukemogenic Mechanism in AML.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 3380-3380
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 3380-3380
    Abstract: Background: We recently identified a novel fusion protein, MLL-CALM, in an infant with fatal AML. Although disruption of normal MLL function clearly contributes to leukemogenesis, perturbed CALM function may also be important. The native CALM protein plays a key role in clathrin-dependent endocytosis (CDE) and intracellular vesicle transport. Interestingly, CALM was first described as a partner for the AF10 gene - itself an MLL partner - in aggressive leukemias and lymphomas. Recently, it was shown that mutations in calm are responsible for hematopoietic abnormalities in inbred fit1 mice. Taken together, these observations suggest an important role for CALM in both normal and malignant hematopoiesis. We hypothesize that disrupted CDE resulting from the presence of CALM-containing fusion proteins interferes with downregulation of growth factor signaling, thereby contributing to leukemogenesis. Objective: 1) To determine whether expression of MLL-CALM or CALM-AF10 interferes with endocytosis of transferrin (TF), 2) To analyze the importance of distinct CALM domains which affect endocytosis, and 3) To determine whether MLL-CALM expression reduces the IL-3 growth factor dependence of FL5.12 cells. Design/Methods: The relative ability of leukemia cell lines that harbor MLL and CALM translocations to endocytose AlexaFluor633-conjugated TF was assessed by flow cytometry. The degree of Texas Red (TR)-TF endocytosis in COS7 cells expressing GFP-tagged MLL-CALM and CALM-AF10 was quantitated using densitometry. CALM deletion constructs were prepared and endocytosis of Texas Red-TF was examined in COS-7 cells transfected with these plasmids. Finally, IL-3-dependent FL5.12 cells engineered to stably express MLL-CALM were grown in decreasing amounts of IL-3-containing WEHI conditioned medium and survival was determined. Results: U937 and P31/Fujioka cells (that harbor the CALM-AF10 translocation) showed reduced endocytosis of AF633-TF, but cells that lack CALM translocations (THP-1, K562, MonoMac6, HL-60) showed robust AF633-TF uptake. COS7 cells expressing MLL-CALM or CALM-AF10 showed 40–50% less endocytosis of TR-TF compared with untransfected cells or cells transfected with empty vector. CALM aa 484–620 appear to be important in inhibiting endocytosis. IL-3-dependent FL5.12 cells transfected with an MLL-CALM expression vector grew better in low concentrations of IL-3-containing WEHI conditioned media in comparison with FL5.12 cells transfected with empty vector. Conclusions: Expression of MLL-CALM or CALM-AF10 interferes with endocytosis, and MLL-CALM expression renders FL5.12 cells less dependent on exogenous IL-3. The ability of MLL-CALM and CALM-AF10 to interfere with CDE may result in sustained growth factor signaling and contribute to the development of aggressive hematopoietic malignancies.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.3380.3380
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 8
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    Online Resource
    The CALM/AF10 Fusion: Molecular Analysis of the Fusion Transcripts in 13 Cases of AML and ALL; Gene Expression Profiling Reveals HOX Gene Deregulation.
    American Society of Hematology ; 2004
    In:  Blood Vol. 104, No. 11 ( 2004-11-16), p. 2895-2895
    Details
    In: Blood, American Society of Hematology, Vol. 104, No. 11 ( 2004-11-16), p. 2895-2895
    Abstract: The t(10;11)(p13;q14) is a recurring translocation associated with the CALM/AF10 fusion gene which is found in undifferentiated leukemia, acute myeloid leukemia, acute lymphoblastic leukemia and malignant lymphoma with poor prognosis. The CALM/AF10 fusion protein was reported to be the most common fusion protein in T-ALL with TCR gamma delta rearrangement. We have analyzed samples from 9 patients with different types of leukemia: case 1 (AML M2), case 2 (AML M0), case 3 (Pre T-ALL), case 4 (Acute Undifferentiated Leukemia), case 5 (PreT-ALL), case 6 and 7 (ProT-ALL), case 8 (T-ALL), case 9 (AML), with a t(10;11) translocation suggesting a CALM/AF10-rearrangement. The samples were analyzed for the presence of the CALM/AF10 and AF10/CALM mRNA by RT-PCR and sequence analysis. All these patients were found positive for the CALM/AF10 fusion. In addition, we analyzed a series of twenty-nine patients with T-ALL with gamma delta rearrangement. Among these patients, four were positive for CALM/AF10 transcripts, indicating a high incidence of CALM/AF10 fusions in this group of leukemia. We found three different breakpoints in CALM at nucleotide 1926, 2091 and a new exon, with 106 bases inserted after nt 2064 of CALM in patient 4. In AF10 four breakpoints were identified: at nucleotide position 424, 589, 883 and 979. In seven patients it was also possible to amplify the reciprocal AF10/CALM fusion transcript (case 1, 3, 4, 8, 9, 10 and 11). There was no correlation between disease phenotype and breakpoint location. The patients were 5 to 46 years old (median 25). Ten CALM/AF10 positive patients were further analyzed using oligonucleotide microarrays representing 33,000 different genes (U133 set, Affymetrix). Analysis of microarray gene expression signatures of these patients revealed high expression levels of the homeobox gene MEIS1 and the HOXA cluster genes HOXA1, HOXA4, HOXA5, HOXA7, HOXA9, and HOXA10. The overexpression of HOX genes seen in these CALM/AF10 positive leukemias is reminiscent of the pattern seen in leukemias with rearrangements of the MLL gene, and complex aberrant karyotypes suggesting a common effector pathway (i.e. HOX gene deregulation) for these diverse leukemias. It is known that alhambra, the Drosophila homologue of AF10 can act on polycomb group responsive elements, which play a critical role in the regulation of the HOX gene clusters. It is thus conceivable that the CALM/AF10 fusion proteins acts in a dominant negative fashion on wild type AF10 function relieving the repression that is presumably normally exerted by AF10 on the expression of HOX genes.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    URL: Article
    DOI: 10.1182/blood.V104.11.2895.2895
    RVK:
    XA 33000
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2004
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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