Hybrid transcription factors, resulting from gene fusions in the wake of chromosomal translocations, have been implicated in leukemogenesis, but their precise contributions to oncogenic conversion remain unclear. The E2A-HLF fusion gene, formed by a t(17;19)(q22;p13) in childhood pro-B-cell acute lymphoid leukemia, encodes a hybrid protein that contains the trans-activation domain of E2A (E12/E47) linked to the bZIP DNA-binding and dimerization domain of hepatic leukemia factor (HLF). Here we report that both HLF and E2A-HLF bind to a 10-bp consensus sequence, 5'-GTTACGTAAT-3', with a core dyad-symmetric motif characteristic of the bZIP scissors-grip model of DNA binding. A probe containing this sequence bound chimeric E2A-HLF proteins in nuclear extracts of a leukemic cell line (UOC-B1) containing the t(17;19), as demonstrated by complexes supershifted with antibodies specific for amino-terminal epitopes of E2A or carboxyl-terminal eptiopes of HLF. E2A-HLF functioned as a potent trans activator of reporter gene expression from a plasmid that contained the consensus DNA-binding sequence. Interestingly, wild-type HLF was restricted in its capacity to act as a trans activator, functioning in human fetal kidney cells but not HepG2 hepatocarcinoma cells or NIH 3T3 mouse fibroblasts. The ability of the E2A-HLF hybrid protein to bind DNA in a sequence-specific manner and trans activate the expression of artificial reporter genes suggests that it could subvert transcriptional programs that normally control the growth, differentiation, and survival of lymphoid progenitor cells.
BACKGROUND Familial hemophagocytic lymphohistiocytosis HLH (FHL) is fatal, unless patients are rescued with hematopoietic stem cell transplantation (SCT). Although the molecular identification of FHL now is possible at least in part from perforin gene study, many cases escape detection or never are tested due to the lack of specific hallmarks, making diagnosis difficult. To the authors' knowledge, it remains to be determined whether persistently low natural killer cell (NK) activity and a high incidence of central nervous system (CNS) disease increase the probability of FHL. METHODS The authors analyzed 42 HLH patients age < 2 years, 13 of whom developed overt CNS disease and 5 of whom demonstrated persistently deficient NK activity (Group 1). The remaining 24 patients had no CNS disease and had NK activity of moderate decrease to within the normal range (Group 2). RESULTS In Group 1, CNS symptoms were detected in 6 cases within 1 month and between 4.5–9 months in 6 other patients. In these cases, spotty lesions demonstrating a high T2 signal in the white matter were noted on brain magnetic resonance imaging. The survival was significantly poor for patients in Group 1 unless they were rescued with SCT, which was performed in 5 of the 13 patients with CNS disease and in all 5 patients with persistent NK activity deficiency. SCT was successful in 9 patients, with no CNS sequelae reported after the transplantation. Conversely, the prognosis of the 24 patients in Group 2 was better and only 1 patient required SCT. CONCLUSIONS Very young HLH patients (age < 2 years) who are at high risk of fatal FHL with persistently deficient NK activity and/or overt CNS disease require appropriate SCT to reverse CNS disease and achieve a complete cure. Cancer 2002;94:3023–31. © 2002 American Cancer Society. DOI 10.1002/cncr.10515
In pro-B cell acute lymphoblastic leukemia (ALL), expression of the E2A-HLF fusion gene as a result of t(17;19)(q22; p13) is associated with poor prognosis, hypercalcemia, and hemorrhagic complications. We previously reported that the E2A-HLF fusion protein protects interleukin-3 (IL-3)-dependent lymphoid cells from apoptosis caused by cytokine starvation. Here, we report that annexin II, a surface phospholipid-binding protein and one of the proposed causes of the hemorrhagic complications of acute promyelocytic leukemia (APL), is also implicated in t(17;19) ؉ ALL. Annexin II was expressed at high levels in APL cells and in each of 4 t(17;19) ؉ leukemia cell lines, and annexin II expression was induced by enforced expression of E2A-HLF in leukemia cells. In IL-3-dependent cells, we found that annexin II expression was regulated by IL-3 mainly by Ras pathways, including IntroductionThe E2A-HLF fusion transcription factor, which is generated by the t(17;19)(q22;p13) translocation, is found in some cases of pro-B cell acute lymphoblastic leukemia (ALL) that occur in older children and adolescents. 1,2 In this chimeric molecule, the transactivation domain of E2A is fused to the basic region and the leucine zipper (bZIP) domain of HLF, which mediate DNA binding and dimerization. Two distinct types of genomic rearrangements resulting in E2A-HLF fusion have been described in t(17;19) ϩ ALL. [1][2][3][4] In type 1 rearrangements, an insertion that codes for a portion of the chimera not found in either wild-type protein occurs between E2A exon 13 and HLF exon 4. This insertion, derived from a cryptic exon spanning the 17;19 breakpoint, contains E2A intronic sequences at its 5Ј end, HLF intronic sequences at its 3Ј end, and various numbers of nontemplated nucleotides in the middle. The type 2 rearrangements arise from more 5Ј breakpoints in E2A and result in a fusion with E2A exon 12 spliced directly to HLF exon 4. The leukemias associated with the E2A-HLF fusion protein do not respond well to intensive chemotherapy, not even the aggressive conditioning for bone marrow transplantation. Moreover, these leukemias frequently manifest with intravascular coagulopathy and hypercalcemia, which are generally rare complications in children with pro-B ALL. 3,5 Table 1 6-9 summarizes the features of all reported t(17;19) ϩ ALLs that have been molecularly analyzed to date. Although the DNA-binding activities and the transcriptional activation properties of the type 1 and type 2 E2A-HLF fusion proteins appear to be similar, coagulopathy develops more frequently among patients with a type 1 rearrangement than among those with type 2. 4,10 We previously demonstrated that E2A-HLF blocks apoptosis in cytokine-deprived murine interleukin-3 (IL-3)-dependent B precursor cells, suggesting that this fusion protein contributes to leukemogenesis by substituting for the antiapoptotic function of cytokines. 11,12 IL-3 supports cell survival through 2 distinct signaling pathways. One pathway acts through the proximal portion of the common  (c) c...
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