Transcription factor fusions in acute leukemia: variations on a theme

Scandura, Joseph M.; Boccuni, Piernicola; Cammenga, Jörg; Nimer, Stephen D.

doi:10.1038/sj.onc.1205315

Cited by 97 publications

(58 citation statements)

References 300 publications

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“…(B) Ideograms of the chromosomes involved displaying the relative location of the breakpoints, the different fragments which were rearranged to generate the complex aberration, and the genes involved. the nuclear rim [24,25], suggests that inappropriate interactions with key transcriptional regulatory proteins required for myeloid differentiation may occur [26]. No other fusion transcripts involving NUP98 or HOXA9 were detected in our patient, confirming the crucial role suggested for the NUP98-HOXA9 transcript in the oncogenesis.…”

Section: Resultssupporting

confidence: 62%

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

Lahortiga

Belloni

Vázquez

et al. 2005

Cancer Genetics and Cytogenetics

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Section: Resultssupporting

confidence: 62%

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

Lahortiga

Belloni

Vázquez

et al. 2005

Cancer Genetics and Cytogenetics

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“…A deletion of the RHD domain identical to the one used in our study has been shown to abolish binding of TEL-AML1 to AML1 target sequences (Uchida et al, 1999). However, the RHD domain is also responsible for binding CBFb, the non-DNA-binding heterodimerization partner of AML1, and transcription factors such as ETS proteins, Smads and CCAAT/enhancer binding proteina (Scandura et al, 2002). In order to establish whether the DNA binding function of the RHD domain is important for TEL-AML1 function, we made a TEL-AML1 construct with a point mutation in the RHD which disrupts DNA but not CBFb binding.…”

Section: Domain Analysis Of Tel-aml1 M Morrow Et Almentioning

confidence: 63%

“…An RHD mutation disrupting DNA binding abrogates TEL-AML1 activity Although the RHD deletion has previously been shown to abrogate DNA binding of TEL-AML1 (Uchida et al, 1999), this domain is also responsible for binding CBFb, the non-DNA-binding heterodimerization partner of AML1 (Scandura et al, 2002). In order to determine which function of the RHD is required for TEL-AML1 activity, the colony forming ability of c-Kit þ cells transduced with the MSCV-R201Q construct was analysed.…”

Section: Expression Of Domain Deletion Mutants Of Tel-aml1 Using Retrmentioning

confidence: 99%

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

Morrow

Samanta

Kioussis³

et al. 2007

Oncogene

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The t(12;21)(p13;q22) translocation generates the TEL-AML1 (TEL, translocation-Ets-leukemia; AML1, acute myeloid leukemia-1) (ETV6-RUNX1) fusion product and is the most common chromosomal abnormality in pediatric leukemia. Our previous studies using a murine fetal liver transplantation model demonstrated that TEL-AML1 promotes the self-renewal of B-cell precursors in vitro and enhances the expansion of hematopoietic stem cells (HSCs) in vivo. This is consistent with the hypothesis that TEL-AML1 induces expansion of a preleukemic clone. Several studies have described domains within TEL-AML1 involved in the transcriptional regulation of specific target genes. However, it is unclear which of these domains is important for the activity of TEL-AML1 in preleukemic hematopoiesis. In order to examine this, we have generated a panel of deletion mutants and expressed them in HSCs. These experiments demonstrate that TEL-AML1 requires multiple domains from both TEL and AML1 to alter hematopoiesis. Furthermore, mutation of a single amino-acid residue within the runt homology domain of AML1, required for DNA binding, was sufficient to abrogate TEL-AML1 activity. These data suggest that TEL-AML1 acts as an aberrant transcription factor to perturb multiple pathways during hematopoiesis.

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“…Mutations or aberrant expression of both transcription factors and signal transducers that play important roles in hematopoiesis and organismal development are frequently found in these myeloblastic leukemias (Gilliland and Griffin, 2002;Scandura et al, 2002). However, the molecular mechanisms by which these genetic alterations act in leukemogenesis are poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice

Cuenco

Ren

2004

Oncogene

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We have previously shown that BCR/ABL, a fusion protein generated by the t(9;22)(q34;q11) translocation found in the vast majority of chronic myelogenous leukemia (CML), cooperates with AML1/MDS1/EVI1 (AME), a fusion transcription factor generated by a t(3;21)(q26;q22) translocation identified as a secondary mutation in some cases of CML during the blast phase (CML-BC), in the rapid induction of an acute myelogenous leukemia (AML) in mice. In this study, we evaluated the leukemogenic potential of EVI1-, MDS1/EVI1-and AML1-related oncoproteins (AML1D, AML1/MDS1). We found that ectopic expression of either EVI1 or MDS1/EVI1 impaired hematopoiesis. However, neither EVI1 nor MDS1/EVI1 was sufficient for inducing AML in mice, although EVI1 did induce some hematologic neoplasia other than AML with a low efficiency. In addition, unlike AME, none of the EVI1-or AML1-related oncoproteins examined were capable of fully cooperating with BCR/ABL in the induction of AML. The results indicate that both the AML1 and EVI1 oncogenic components are required for the leukemogenic potential of AME and for the cooperation of AME and BCR/ABL in the induction of AML.

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Transcription factor fusions in acute leukemia: variations on a theme

Cited by 97 publications

References 300 publications

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

NUP98 is fused to HOXA9 in a variant complex t(7;11;13;17) in a patient with AML-M2

TEL-AML1 preleukemic activity requires the DNA binding domain of AML1 and the dimerization and corepressor binding domains of TEL

Both AML1 and EVI1 oncogenic components are required for the cooperation of AML1/MDS1/EVI1 with BCR/ABL in the induction of acute myelogenous leukemia in mice

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