Molecular Characterization of the Translocation (10;11)(p13;q14): MLLandCALMare Fused toAF10in Morphologically Different Subsets of Acute Leukemia

Abstract

The t(10,11)(pl3;ql4) is a recurring translocation that has been observed in acute lymphoblastic as well as acute myeloid leukemia. A previous study revealed a MLL/AF10fusion in all cases of AML with t(10;11) and various breakpoints on chromosome 11 ranging from ql3 to q23. In contrast, we recently cloned CALM(Clathrin Assembly Lymphoid Myeloid leukemia gene), another fusion partner of AF10located at 11q14, in the monocytic cell line U937. To further define the role of these genes in acute lymphoblastic and acute myeloid leukemia, we analyzed 10 patient samples (9 AML, 1 ALL) with cytogenetically identified t(10;11)(pl2–14;ql3–21) and well characterized morphology and immunophenotype. Interphase fluorescence in situhybridization (FISH) was performed using YAC probes flanking the breakpoint regions. In all cases with simple t(10;11) tested, AF10was involved whereas in 2 cases with complex translocations, no rearrangement of AF10, MLLor CALMwas detected. In 4 cases including one secondary AML (1 AML-MO, 2 AML-M1,1 ALL), the signals of the CALMYACS were separated in interphase cells indicating a translocation breakpoint within theCALMregion. In all of these cases, RT-PCR revealed CALM/AF10fusions containing virtually the whole coding region of CALMand AF10.In 2 of 4 cases different splice variants were identified. The reciprocal AF10/CALMfusion was detected in all 3 cases of AML, but not in the one ALL patient. FISH identified a MLLrearrangement in 3 cases (2 AML-M2, 1 AML-M5). In one additional case (AML-M5), RT-PCR detected a fusion product between MLL/exon 7 and AF10.The different morphology of AML with either CALM (immature phenotype) or MLL(myelomonocytic differentiation) rearrangement corresponded to a characteristic immunophenotype. We conclude that CALM and MLL rearrangement identify morphologically different subsets of acute leukemia with t(10;11)(pl3;ql4). However, functional studies are necessary to elucidate the biological role of the fusion products in leukemogenesis.