We showed that the LAF4 gene on 2q11.2-12 was fused to the MLL gene on 11q23 in a pediatric patient with CD10 positive acute lymphoblastic leukemia (ALL) having t(2;11)(q11;q23). The LAF4 gene, which encodes a lymphoid nuclear protein of 1227 amino acids with transactivation potential, is thought to have a role in early lymphoid development. The LAF4 protein was homologous to AF4 and AF5q31 proteins that are fused to MLL in infant early pre-B ALL and the breakpoint of LAF4 was located within the region homologous to the transactivation domain of AF4 and AF5q31. Expression of the 8.5-kb LAF4 transcript was detected in the adult heart, brain, and placenta and in the fetal brain. LAF4 expression was found to be higher in ALL cell lines than in AML and Epstein-Barr virus-transformed B-lymphocyte cell lines. These findings suggest that LAF4, AF4 and AF5q31 might define a new family particularly involved in the pathogenesis of 11q23-associated ALL.
In the treatment of childhood acute lymphoblastic leukemia (ALL), excess shortening of maintenance therapy resulted in high relapse rate, as shown by our previous trial, TCCSG L92-13, in which maintenance therapy was terminated at 1 year from initiation of treatment. In this study, we aimed to confirm the long-term outcome of L92-13, and to identify who can or cannot be cured by shorter duration of maintenance therapy. To obtain sentinel cytogenetics information that had been missed before, we performed genetic analysis with genomic microarray and target intron-capture sequencing from diagnostic bone marrow smear. Disease-free survival (DFS) at 10 years from the end of therapy was 66.0±2.8%. Females (n=138) had better DFS (74.6±3.7%) than males (n=142, 57.5±4.2%, P=0.002). Patients with TCF3-PBX1 (n=11) and ETV6-RUNX1 (n=16) had excellent DFS (90.9±8.7% and 93.8±6.1%, respectively), whereas high hyperdiploidy (n=23) was the most unfavorable subgroup, with 56.6±10.3% of DFS. Short duration of therapy can cure more than half of pediatric ALL, especially females, TCF3-PBX1 and ETV6-RUNX1. Our retrospective observations suggest a gender/karyotype inhomogeneity on the impact of brief therapy.
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...
The E2A-HLF fusion transcription factor generated by t(17;19)(q22;p13) translocation is found in a small subset of pro-B cell acute lymphoblastic leukemias (ALLs) and promotes leukemogenesis by substituting for the antiapoptotic function of cytokines.
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