Identification of a novel fusion gene in a pre‐B acute lymphoblastic leukemia with t(1;19)(q23;p13)

Abstract

The most common nonrandom translocation found among childhood pre-B acute lymphoblastic leukemias (ALL) is t(1;19)(q23;p13), which frequently results in fusion of E2A with PBX1. However, rare cases of childhood ALL and various other hematological diseases with t(1;19) lack the E2A-PBX1 fusion. Analyzing a cell line with pre-B-cell phenotype, TS-2, that carries t(1;19)(q23;p13) but lacks the E2A-PBX1 fusion, we successfully cloned the breakpoints, which fell within introns of MEF2D and DAZAP1. Both chimeric transcripts, MEF2D-DAZAP1 and DAZAP1-MEF2D, whose sequences indicated in-frame fusions between MEF2D and DAZAP1, were expressed in TS-2 cells and in bonemarrow cells of the patient from whom the TS-2 was established. MEF2D-DAZAP1 and DAZAP1-MEF2D proteins were both located in the nucleus, and MEF2D-DAZAP1 was able to form dimers with MEF2D and HDAC4. In addition, exogenous expression of MEF2D-DAZAP1 and DAZAP1-MEF2D promoted the growth of HeLa cells. Given the frequency of t(1;19) without the E2A-PBX1 fusion in hematological malignancies, we suggest that MEF2D/DAZAP1 rearrangements might be involved in the pathogenesis of those diseases. (Cancer Sci 2004; 95: 503-507) he most common type of childhood leukemia is acute lymphoblastic leukemia (ALL), which has a B-cell precursor phenotype.1) The main subtypes of ALL involve multiple genetic alterations including point mutations and deletions, and are also characterized by gross chromosomal changes such as translocations, which are likely to cause illegitimate recombination or juxtaposition of normally separated genes. In leukemias an in-frame fusion gene is often created, generating a hybrid protein with altered properties. Although more than 200 genes are known to be involved in translocations in leukemias, certain genes predominate in those events and the others are involved only rarely. 1)The most common nonrandom translocation in childhood pre-B ALL is t(1;19)(q23;p13), usually involving fusion between PBX1 at 1q23 and E2A at 19p13.3. The chimeric gene, E2A-PBX1, encodes a protein that contains the transactivation domain of E2A and the DNA-binding homeodomain of PBX1. 2)Although an identical E2A-PBX1 chimeric gene can be detected in more than 95% of ALL cases with t(1;19), in rare cases the E2A-PBX1 fusion gene is absent. 3,4)

Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2D fusion proteins generated by the variant t(1;19) in acute lymphoblastic leukemia

“…4 We observed that DAZAP1 protein, which did not induce anchorage-independent growth, consistently accumulated to very high levels relative to DAZAP1/MEF2D and MEF2D/DAZAP1 fusion proteins Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2 V Prima and SP Hunger (Figure 1c). It was unclear whether this was because of more efficient transcription/translation, enhanced stability or reduced toxicity of the protein.…”

“…14 The location of MEF2D at the breakpoint of a chromosome translocation in human acute lymphoblastic leukemia, 4,5 and the current studies demonstrating potent transforming properties of both resultant MEF2D protein chimeras establish that MEF2D has latent oncogenic properties. Members of MEF2 protein family interact with a variety of other Cooperative transformation by MEF2D/DAZAP1 and DAZAP1/MEF2 V Prima and SP Hunger proteins involved in transcriptional regulation including histone deacetylases, p300 and Cabin1/Cain.…”

“…4,5 MEF2D is a member of the MEF2 family of DNA-binding proteins, which activate transcription of genes involved in control of differentiation and survival of lymphoid, neural and muscle cells. 6 DAZAP1 is a novel RNA-binding protein involved in mRNA processing/trafficking that is expressed most abundantly in testis.…”

MEF2C is activated by multiple mechanisms in a subset of T-acute lymphoblastic leukemia cell lines

“…Expression of both MEF2C and MEF2D occurs in lymphocytes, while that of MEF2C is restricted to B-cells, implying that activation in T-ALL cells may require dysregulation. 43 In pre-B-ALL, t(1;19)(q23;p13) results in the fusion of MEF2D with DAZAP1 shown to be involved in pathogenesis, 44,45 supporting the notion of leukemic potential among MEF2-proteins.…”

Class IIa histone deacetylases: regulating the regulators

“…It is now essential to establish whether alterations of the class IIa HDAC-MEF2 axis occur in these human pathologies. Genetic alterations of MEF2 family members have been linked to cardiovascular diseases (Wang, 2005;Visvikis-Siest and Marteau, 2006) and acute lymphoblastic leukemia (Yuki et al, 2004;Prima et al, 2005). Similarly, alterations of MEF2 transcriptional activity have been implicated in neurodegenerative disorders (Camins et al, 2006) and cardiac hypertrophy (Czubryt and Olson, 2004).…”