Fusion of the Leucine Zipper Gene
            <i>HLF</i>
            to the
            <i>E2A</i>
            Gene in Human Acute B-Lineage Leukemia

Inaba, Toshiya; Wm, Roberts; Shapiro, LH; Kw, Jolly; Raimondi, SC; Sd, Smith; At, Look

doi:10.1126/science.1386162

Cited by 272 publications

(209 citation statements)

References 26 publications

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“…As a result of the t(17;19)(q22;p13), the E2A gene is fused to the HLF gene on chromosome 17 (Inaba et al, 1992). In the E2A-HLF chimeric gene product, the transactivation domain of E2A is fused to the basic region/leucine zipper domain of hepatic leukemia factor (HLF), which contributes to the DNA binding and dimerization (Inaba et al, 1992). Clinically, ALL with the E2A-HLF chimera is refractory to intensive therapy and is frequently associated with coagulopathy and hypercalcemia (Hunger, 1996).…”

Section: Introductionmentioning

confidence: 99%

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: 99%

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

et al. 2010

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“…For example, mammalian GLI-1 was originally identified as a protooncogene amplified in glioblastomas (Ruiz i Altaba et al, 2002). The ces-2-like proto-oncogene HLF was identified at the breakpoint of a t(17;19) chromosomal translocation found in patients with pro-B-cell acute lymphoblastic leukemia and the ceh-20-like proto-oncogene PBX-1 was identified at the breakpoint of a t(1;19) chromosomal translocation found in patients with pre-Bcell acute lymphoblastic leukemia (Kamps et al, 1990;Nourse et al, 1990;Hunger et al, 1992;Inaba et al, 1992). Finally, the CEP-1-like mammalian p53 protein is a tumor suppressor that is found to be inactivated in the majority of human tumors (Pietsch et al, 2008).…”

Section: Apoptosis and Tumorigenesismentioning

confidence: 99%

egl-1: a key activator of apoptotic cell death in C. elegans

Nehme

Conradt

2008

Oncogene

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Since the discovery of mammalian BIK and BAD in 1995, BH3-only proteins have emerged as key activators of apoptotic cell death in animals as diverse as the nematode, Caenorhabditis elegans, and humans. BH3-only proteins have also emerged as integrators of cell-death signals that determine the life-versus-death decision and that transduce this decision to the central apoptotic machinery through their physical interaction with 'core' BCL-2 family members, such as BCL-2 or BCL-XL. Currently, eight BH3-only proteins have been identified and characterized in mammals, and there is evidence of functional overlap between them. In contrast, only two BH3-only proteins have so far been identified and characterized in C. elegans, EGL-1 and CED-13, and there seems to be only limited functional overlap between them. Combined with the powerful genetic tools available for the analysis of apoptosis in C. elegans, and the ability to study apoptosis at single-cell resolution in this organism, the absence of extensive functional redundancy makes C. elegans an ideal model for studies on BH3-only proteins. In this study, we will review our current understanding of the role and regulation of EGL-1. We will also briefly summarize studies on CED-13, which was identified more recently.Oncogene ( Keywords: BCL-2 family; BH3-only proteins; apoptosis; C. elegans; EGL-1; CED-13The egl-1 storyThe egl-1 gene was originally defined by dominant, gain of function (gf) mutations (Trent et al., 1983;Ellis and Horvitz, 1986). These gf mutations cause the hermaphrodite-specific neurons (referred to as 'HSNs'), which are required for egg laying in Caenorhabditis elegans hermaphrodites, to inappropriately die. egl-1 gf mutations were identified in screens for egg-laying defective or 'Egl' animals, and were carried out in Bob Horvitz's laboratory in the early 1980s (hence the name 'egl-1'). These 'Egl screens' resulted in the identification of a total of seven egl-1 gf mutations. Three of these mutations (n487, n1084 and n1796) cause an Egl phenotype in a semi-dominant manner, and the remaining four mutations (n986, n987, n2164 and n2248) cause an Egl phenotype in a fully dominant manner. The inappropriate death of the HSNs in egl-1 gf mutants can be suppressed by mutations that cause a general block in apoptotic cell death, such as a gf mutation in ced-9, which encodes an anti-apoptotic BCL-2-like protein, or loss-of-function (lf) mutations in either ced-4 or ced-3, which encode an APAF-1-like adapter or a caspase, respectively (Ellis and Horvitz, 1986;Hengartner et al., 1992;Yuan and Horvitz, 1992;Yuan et al., 1993;Hengartner and Horvitz, 1994b). These findings showed that the HSNs in egl-1 gf animals inappropriately die by apoptosis. They also suggested that the egl-1 gene may act upstream of the anti-apoptotic gene, ced-9, and of the pro-apoptotic genes, ced-4 and ced-3; however, the normal function of egl-1 remained unclear because of the lack of egl-1 lf mutations. The lack of egl-1 lf mutations not only made it difficult to determine the normal f...

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“…[1][2][3][4][5][6][7] E2A encodes for proteins (E47/E12/E2-5) belonging to a family of eukaryotic transcriptional regulators characterized by the basic helix-loop-helix motif. 8 PBX1 and HLF, identified by virtue of their rearrangement with E2A, appear to be transcriptional regulators as well.…”

Section: Introductionmentioning

confidence: 99%

“…4,5 HLF encodes for proteins of the PAR subfamily of the bZip transcription factors and is not expressed in lymphocytes, as well. 6,7 The genomic breakpoints leading to the t(1;19) generally occur in one intron of E2A (intron 13), but rare exceptions. [9][10][11] As to PBX1, the breakpoints are similarly clustered in one intron and the gene exonic structure provides the in-frame fusion with the E2A coding sequence.…”

Section: Introductionmentioning

confidence: 99%

“…12 More complex rearrangements occur at the genomic breakpoints of the (17;19), with the involvement of either E2A exon 12 or exon 13, the splicing of a cryptic exon and the addition of random nucleotides that provide the maintenance of the open reading frame in the chimeric mRNA. 6,7,13 The chimeric genes E2A-PBX1 and E2A-HLF are expressed in chimeric proteins that retain the transactivation domain of E2A but substitute either the homeobox domain of PBX1 or the bZip domain of HLF for the bHLH domain of E2A, 4-7 displaying altered transcriptional properties and transforming potential in NIH 3T3 cells. 7,[14][15][16][17][18][19][20][21] The E2A proteins are widely expressed and form heterodimers with tissue-restricted bHLH partners, that may influence their DNA-binding affinity.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

True

1999

Leukemia

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The 'promiscuous' E2A gene, at 19p13.3, is fused with two different molecular partners, PBX1 and HLF, following two chromosome translocations recurrent in childhood pre-B ALL. We have identified a novel gene, FB1, by virtue of its fusion with E2A and by a combination of molecular techniques. FB1 was localized on 19q13.4, suggesting that the novel chimera originated by a cryptic rearrangement of chromosome 19. Two FB1 transcripts, of 1.2 kb and 1.1 kb, are differentially expressed at low level in a variety of human tissues, including hemopoietic cell lines from different lineages. Accordingly, FB1 cDNA displays high homology with a number of cDNA clones from different human tissues. High homology was found also with cDNA clones from mouse and rat, suggesting that the sequence might be conserved at least among mammals. The function of the putative FB1 protein, however, is currently unknown as database sequence comparisons have failed to reveal strong homology with known proteins. The E2A/FB1 fusion appears to be a recurrent feature of pre-B ALLs, suggesting that it might have a role in the development and/or progression of leukemogenesis.

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Fusion of the Leucine Zipper Gene HLF to the E2A Gene in Human Acute B-Lineage Leukemia

Cited by 272 publications

References 26 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

egl-1: a key activator of apoptotic cell death in C. elegans

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