AML1-FOG2 fusion protein in myelodysplasia

Chan, Edward M.; Comer, Elisha M.; Brown, Frances C.; Richkind, Kathleen E.; Holmes, Melissa L.; Chong, Beng H.; Shiffman, Roger; Zhang, Dong Er; Slovak, Marilyn L.; Willman, Cheryl L.; Noguchi, Constance Tom; Li, Yanjun; Heiber, Devan J.; Kwan, Lori; Chan, Rebecca J.; Vance, Gail H.; Ramsey, H. E.; Hromas, Robert

doi:10.1182/blood-2004-07-2762

Cited by 29 publications

(20 citation statements)

References 21 publications

(17 reference statements)

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“…All in-frame chimeras have RUNX1 in the 5 0 position. [13][14][15][16]28 This results in proteins that retain the CBFB-and DNA-binding RUNT domain but lose the transactivation (TA) domain of RUNX1. Several of these fusions have been shown to act as dominant-negative inhibitors of normal RUNX1 function; 8 the same is true for some mutations.…”

Section: Discussionmentioning

confidence: 99%

“…To date, five in-frame fusion gene partners have been reported: RUNX1T1 (previously ETO, MTG8, CBFA2T1) at 8q22, 12 MDS1/EVI1 at 3q26, 13 CBFA2T3 (previously MTG16) at 16q24, 14 PRDX4 at Xp22, 15 and ZFPM2 (previously FOG2) at 8q23. 16 The translocations resulting in these fusions have all been detectable with G-banding. In the present study, we describe a novel and cytogenetically cryptic t(7;21)(p22;q22) in AML, fusing RUNX1 with the ubiquitinspecific protease (USP) gene USP42, which is involved in the ubiquitin pathway.…”

Section: Introductionmentioning

confidence: 99%

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A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

et al. 2005

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Although many of the chromosomal abnormalities in hematologic malignancies are identifiable cytogenetically, some are only detectable using molecular methods. We describe a novel cryptic t(7;21)(p22;q22) in acute myeloid leukemia (AML). FISH, 3 0 RACE, and RT-PCR revealed a fusion involving RUNX1 and the ubiquitin-specific protease (USP) gene USP42. The genomic breakpoint was in intron 7 of RUNX1 and intron 1 of USP42. The reciprocal chimera was not detected -neither on the transcriptional nor on the genomic level -and FISH showed that the 5 0 part of USP42 was deleted. USP42 maps to a 7p22 region characterized by segmental duplications. Notably, 17 kb duplicons are present 1 Mb proximal to USP42 and 3 Mb proximal to RUNX1; these may be important in the genesis of t (7;21). This is the second cryptic RUNX1 translocation in hematologic malignancies and the first in AML. The USPs have not previously been reported to be rearranged in leukemias. The cellular context in which USP42 is active is unknown, but we here show that it is expressed in normal bone marrow, in primary AMLs, and in cancer cell lines. Its involvement in the t(7;21) suggests that deregulation of ubiquitin-associated pathways may be pathogenetically important in AML.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

et al. 2005

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“…1,2 AML1 is also the major gene involved in chromosomal translocations in leukemia, 3,4 seen translocated in both lymphoid and myeloid leukemia, such as t(8;21) (AML1-ETO), 5 t(3;21) (AML1-Evi1), 6 t(12;21) (TEL-AML1), 7 t(16;21) (AML1-MTG16), 8 t(12;21) (AML1-copine VIII), 9 t(X;21) (AML1-Fog2), 10 and t(7;21) (AML1-USP42). 11 Specifically the AML1-ETO-associated translocation is observed in approximately 40% of cases of acute myeloid leukemia of the M2 classification (AML-M2), while present in approximately 12% of AMLs.…”

Section: Introductionmentioning

confidence: 99%

The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

Peterson

Yan

Zhang

2007

Blood

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The 8;21 translocation is a major contributor to acute myeloid leukemia (AML) of the M2 classification occurring in approximately 40% of these cases. Multiple mouse models using this fusion protein demonstrate that AML1-ETO requires secondary mutagenic events to promote leukemogenesis. Here, we show that the negative cell cycle regulator p21 WAF1 gene is up-regulated by AML1-ETO at the protein, RNA, and promoter levels. Retroviral transduction and hematopoietic cell transplantation experiments with p21 WAF1 -deficient cells show that AML1-ETO is able to promote leukemogenesis in the absence of p21 WAF1 . Thus, loss of p21 WAF1 facilitates AML1-ETO-induced leukemogenesis, suggesting that mutagenic events in the p21 WAF1 pathway to bypass the growth inhibitory effect from AML1-ETO-induced p21 WAF1 expression can be a significant factor in AML1-ETO-associated acute myeloid leukemia. (RUNX1) is a member of the Runt family of transcription factors that heterodimerize with CBF␤ to form a stable DNAbinding complex. 1,2 AML1 is also the major gene involved in chromosomal translocations in leukemia, 3,4 seen translocated in both lymphoid and myeloid leukemia, such as t(8;21) (AML1-ETO), 5 t(3;21) (AML1-Evi1), 6 t(12;21) (TEL-AML1), 7 t(16;21) (AML1-MTG16), 8 t(12;21) (AML1-copine VIII), 9 t(X;21) (AML1-Fog2), 10 and t(7;21) (AML1-USP42). 11 Specifically the AML1-ETO-associated translocation is observed in approximately 40% of cases of acute myeloid leukemia of the M2 classification (AML-M2), while present in approximately 12% of AMLs. This translocation protein contains the N-terminal portion of AML1 up to its Runt homology DNA-binding domain fused to most of the ETO (MTG8) protein. 12 The ETO gene is one of the family of ETO/MTG repressor proteins that have homology to the Drosophila Nervy repressor proteins. 13,14 Nonconditional AML1-ETO knock-in mice 15,16 are similar to AML1-deficient mice 17,18 in embryonic lethality and in displaying a block in embryonic definitive hematopoiesis, suggestive of a dominant-negative function. Furthermore, directed controlled expression of AML1-ETO in mice demonstrated that AML1-ETO does not promote leukemia under these circumstances. [19][20][21][22] However, following the treatment of AML1-ETO-expressing mice with a DNA-alkylating agent, the mice developed AML. 20,21 Furthermore, various retroviral transduction models have shown again that it does not promote AML. 23,24 These studies suggest that AML1-ETO requires secondary mutagenic events to promote development of AML. Indeed, AML1-ETO promotes AML when combined with the loss of the ICSBP gene, overexpression of WT1, the Flt3-activating mutation, or cotransduction with another translocation fusion protein TEL-PDGFR. [24][25][26][27] The biologic characterization of AML1-ETO in various cell lines has shown that it has both positive and negative effects on leukemia development. Its positive influence comes from its ability to block differentiation and to expand hematopoietic stem cells 23,24,[28][29][30][31][32] ; however, its negat...

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“…2,23 Although there is only 1 additional reported patient with AML with t(8;21)(q24;q22) probably carrying AML1-TRPS1, 6,7 a similar fusion, AML1-FOG2, that represses both AML1-and GATA-1-mediated transactivation, was found in a patient with myelodysplastic syndrome. 24 Moreover, the most pervasive fusion gene in AML, AML1-MTG8, has also been shown to repress GATA-1 function in addition to its dominant-negative effect on AML1. 20,25 Collectively, the concurrent transcriptional deregulation of AML1 and GATA factors in leukemia seems relatively common.…”

Section: Aml1-trps1 In Aml 4025mentioning

confidence: 99%

Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia

Asou

Yanagida

Huang

et al. 2007

Blood

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The Runt domain transcription factor AML1/RUNX1 is essential for the generation of hematopoietic stem cells and is the most frequent target of chromosomal translocations associated with leukemia. Here, we present a new AML1 translocation found in a patient with acute myeloid leukemia M4 with t(8;21)(q24;q22) at the time of relapse. This translocation generated an in-frame chimeric gene consist- IntroductionAML1/RUNX1 encodes the DNA-binding ␣ subunit of the heterodimeric transcription factor PEBP2/CBF, which interacts with the partner ␤ subunit (PEBP2␤/CBF␤) through its evolutionarily conserved Runt domain. 1 AML1 is one of the most frequently mutated genes in human leukemia, 2-4 and was originally identified as a gene on chromosome 21 involved in t(8;21)(q22:q22). 5 To date, 11 AML1-related translocations are known that produce chimeric proteins such as AML1-MTG8/ETO in t(8;21), AML1-EVI1 in t(3;21), and TEL-AML1 in t(12;21). 2,6,7 All these AML1 chimeric proteins retain the Runt domain and inhibit transcriptional activity of wild-type AML1 in a dominant-negative manner. [2][3][4] However, the functional contributions of partner moieties in leukemogenesis remain largely undetermined. Here, we report a new AML1 translocation, t(8;21)(q24;q22), in a patient with acute myeloid leukemia (AML), and present results from functional analyses of the chimeric protein AML1-TRPS1. Patient, materials, and methods Patient profileA 56-year-old Japanese man was diagnosed with AML M4 with a normal karyotype in October 1997. He was treated with idarubicin and cytarabine, followed by postremission therapy according to the Japan Adult Leukemia Study Group (JALSG) AML97. 8 In July 1999, his marrow showed 55.6% blasts with t(8;21)(q24;q22) at relapse. Bone marrow cells at diagnosis and relapse showed the similar morphology and immunophenotypes positive for CD13, CD33, CD4, and HLA-DR, but negative for CD34, which were consistent with AML M4. 9 The study was approved by the Institutional Review Board of Kumamoto University School of Medicine, Japan, and informed consent was obtained from the patient, according to the Declaration of Helsinki. Molecular cloningThe fusion partner gene was cloned by long-distance 3Ј rapid amplification of cDNA ends (RACE) using the SMART RACE kit (Clontech Labs, Mountain View, CA). Plasmid constructionsThe cloned fusion gene AML1-TRPS1 was inserted into the pEF-Bos expression plasmid 10 or MIG retroviral vector. 11 Mutant constructs were generated by polymerase chain reaction (PCR)-based site-directed mutagenesis. EMSAElectrophoretic mobility shift assays (EMSAs) were performed using biotin-labeled probes containing the AML1 12 or GATA factor-binding sites. 13 The specificity of the probes are shown in Figure S1, available on the Blood website (see the Supplemental Figure link at the top of the online article). Whole-cell extracts of COS7 cells (1 ϫ 10 6 ) transfected with pEF-Bos expression vectors were subjected to the assay. Transcription assayThe luciferase reporter constructs pBXH2-LTR-luc and pRBG...

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AML1-FOG2 fusion protein in myelodysplasia

Cited by 29 publications

References 21 publications

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

A novel and cytogenetically cryptic t(7;21)(p22;q22) in acute myeloid leukemia results in fusion of RUNX1 with the ubiquitin-specific protease gene USP42

The p21Waf1 pathway is involved in blocking leukemogenesis by the t(8;21) fusion protein AML1-ETO

Concurrent transcriptional deregulation of AML1/RUNX1 and GATA factors by the AML1-TRPS1 chimeric gene in t(8;21)(q24;q22) acute myeloid leukemia

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