The role of E2A-PBX1 in leukemogenesis

Aspland, Simon E.; Bendall, Heather; Murre, Cornelis

doi:10.1038/sj.onc.1204592

Cited by 120 publications

(79 citation statements)

References 104 publications

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“…Interestingly, the phenotypes of the E2A-HLF transgenic mice closely resembled those of E2A-deficient mice, which also showed abnormal T-cell development, absence of B-cell precursors and rapid development of T-cell lymphomas (Bain et al, 1994(Bain et al, , 1997Zhuang et al, 1994). These results strongly suggested that E2A-HLF contributes to leukemogenesis by activating downstream target genes and/or by suppressing transcriptional activity of endogenous genes in a dominant-negative manner (Aspland et al, 2001;Seidel and Look, 2001).…”

Section: Introductionmentioning

confidence: 74%

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

et al. 2010

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E2A-hepatic leukemia factor (HLF) is a chimeric protein found in B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: growth factor independent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be overexpressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)-positive B-lineage ALL.

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Section: Introductionmentioning

confidence: 74%

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

et al. 2010

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“…PBX1 is already well known as fusion partner of the E2A gene in a subset of ALL cases. 35 PIWIL4 is involved in the maintenance and self-renewal of stem cells, as well as in RNA interference. TCF12 is a transcription factor that associates with E2A to steer somatic recombination of T-cell receptor genes.…”

Section: Reciprocal Mll Gene Fusionsmentioning

confidence: 99%

New insights to the MLL recombinome of acute leukemias

et al. 2009

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Chromosomal rearrangements of the human MLL gene are associated with high-risk pediatric, adult and therapy-associated acute leukemias. These patients need to be identified, treated appropriately and minimal residual disease was monitored by quantitative PCR techniques. Genomic DNA was isolated from individual acute leukemia patients to identify and characterize chromosomal rearrangements involving the human MLL gene. A total of 760 MLL-rearranged biopsy samples obtained from 384 pediatric and 376 adult leukemia patients were characterized at the molecular level. The distribution of MLL breakpoints for clinical subtypes (acute lymphoblastic leukemia, acute myeloid leukemia, pediatric and adult) and fused translocation partner genes (TPGs) will be presented, including novel MLL fusion genes. Combined data of our study and recently published data revealed 104 different MLL rearrangements of which 64 TPGs are now characterized on the molecular level. Nine TPGs seem to be predominantly involved in genetic recombinations of MLL: AFF1/AF4, MLLT3/ AF9, MLLT1/ENL, MLLT10/AF10, MLLT4/AF6, ELL, EPS15/AF1P, MLLT6/AF17 and SEPT6, respectively. Moreover, we describe for the first time the genetic network of reciprocal MLL gene fusions deriving from complex rearrangements.

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“…In addition, the leukemogenic effect of t(1;19)(q23;p13) might also result from a reduced level of wild-type E2A protein, which has recently been shown to have antiproliferative capacity in B-cell progenitors. 57,58 Translocation t(1;19) is generally correlated with a poor prognosis, which can be overcome with more intensive chemotherapy, except for cases with the balanced t(1;19). [14][15][16] In t(17;19)(q22;p13), TCF3 (E2A) is fused to the transcription factor HLF (hepatic leukemia factor) gene, which is found in B1% of precursor-B-ALL (Table 2), especially in a rare form of high risk pro-B-ALL in adolescents.…”

Section: Translocations Involving the Tcf3 (E2a) Gene (19p132-p133)mentioning

confidence: 99%

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

Burg

Poulsen²,

Hunger

et al. 2004

Leukemia

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Chromosome aberrations are frequently observed in precursor-B-acute lymphoblastic leukemias (ALL) and T-cell acute lymphoblastic leukemias (T-ALL). These translocations can form leukemia-specific chimeric fusion proteins or they can deregulate expression of an (onco)gene, resulting in aberrant expression or overexpression. Detection of chromosome aberrations is an important tool for risk classification. We developed rapid and sensitive split-signal fluorescent in situ hybridization (FISH) assays for six of the most frequent chromosome aberrations in precursor-B-ALL and T-ALL. The split-signal FISH approach uses two differentially labeled probes, located in one gene at opposite sites of the breakpoint region. Probe sets were developed for the genes TCF3 (E2A) at 19p13, MLL at 11q23, ETV6 at 12p13, BCR at 22q11, SIL-TAL1 at 1q32 and TLX3 (HOX11L2) at 5q35. In normal karyotypes, two colocalized green/red signals are visible, but a translocation results in a split of one of the colocalized signals. Split-signal FISH has three main advantages over the classical fusionsignal FISH approach, which uses two labeled probes located in two genes. First, the detection of a chromosome aberration is independent of the involved partner gene. Second, split-signal FISH allows the identification of the partner gene or chromosome region if metaphase spreads are present, and finally it reduces false-positivity. Leukemia ( Chromosome aberrations play an important role in hematological malignancies. 1 In ALL, most of these aberrations concern balanced translocations involving genes that play key roles in the development and function of lymphoid cells, such as transcription factors, cell cycle regulators, and signal transduction molecules. Balanced translocations can result in fusion of two genes that encode leukemia-specific chimeric (fusion) proteins. The fusion proteins have functional features that differ from the corresponding wild-type proteins and mostly play a role in leukemogenesis. In addition to the new features of the fusion protein, loss of wild-type activity due to the translocation (in some translocations enhanced by deletion of the second allele) might contribute to oncogenesis. Alternatively, chromosome translocations can result in deregulated expression of (onco)genes as a direct consequence of a translocation to a regulatory element, for example, an immunoglobulin (Ig) or T-cell receptor (TCR) enhancer. 2,3 The most frequent translocations in precursor-B-ALL are t(1;19)(q23;p13) t(4;11)(q21;q23), t(12;21)(p13;q22), and t(9;22)(q34;q11), all four of which result in generation of fusion genes. The t(1;19)(q23;p13) fuses the transcription factorencoding gene TCF3 (E2A) with the transcription factor PBX1. In t(4;11)(q21;q23), the MLL gene at 11q23, which encodes a putative DNA-binding protein, is translocated to the MLLT2 (AF4) gene. The MLL gene is involved in many other translocations in ALL and acute myeloid leukemia (AML). Until now, more than 30 partner genes have been identified. 4 The t(12;21)(p13;q22) involves th...

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The role of E2A-PBX1 in leukemogenesis

Cited by 120 publications

References 104 publications

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

New insights to the MLL recombinome of acute leukemias

Split-signal FISH for detection of chromosome aberrations in acute lymphoblastic leukemia

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