Alternative splicing in wild-type AF10 and CALM cDNAs and in AF10-CALM and CALM-AF10 fusion cDNAs produced by the t(10;11)(p13–14;q14–q21) suggests a potential role for truncated AF10 polypeptides

Abstract

The t(10;11)(p13;q14-21) is a non-random translocation that occurs primarily in T cell acute lymphoblastic leukemias (T-ALL), but has also been observed in leukemias and lymphomas of diverse lineages. In U937, a cell line established from a diffuse histiocytic lymphoma, a t(10;11)(p13;q14-21) fuses AF10 to CALM. AF10 is also fused to MLL by a translocation that appears quite similar at the cytogenetic level, the t(10;11)(p12;q23). Fluorescence in situ hybridization studies have demonstrated that AF10 and CALM are also involved in other hematological malignancies containing t(10;11)(p13;q21), but no data are available concerning the molecular details of AF10-CALM fusion in primary leukemias. Using RT-PCR, we amplified multiple different isoforms of AF10-CALM and CALM-AF10 fusion cDNAs from a primary T cell ALL containing a t(10;11)(p13-14;q14-21). These cDNAs arose via alternative splicing of exons from both AF10 and CALM, which we demonstrated can also occur in the native genes. We identified at least two novel AF10 exons that can be included in wild-type and fusion cDNAs. The majority of the AF10 and AF10-CALM cDNA isoforms that we identified are predicted to encode for truncated AF10 polypeptides, raising the possibility that these might have important cellular functions in normal and malignant cells, perhaps by acting as dominant negative inhibitors of fulllength AF10 or related proteins.

The novel CALM interactor CATS influences the subcellular localization of the leukemogenic fusion protein CALM/AF10

“…Recently, cases of more differentiated AML with a CALM/AF10 fusion have been reported (FAB M4, M5 and M7) (Carlson et al, 2000;Salmon-Nguyen et al, 2000;Jones et al, 2001;Abdou et al, 2002;Nakamura et al, 2003). The translocation is observed in younger patients (Kobayashi et al, 1997;Dreyling et al, 1998;Silliman et al, 1998;Kumon et al, 1999), and is also associated with mixed-lineage immunophenotype with coexpression of lymphoid (T-cell) and myeloid antigens (Kumon et al, 1999;Narita et al, 1999).…”

Identification and molecular characterisation of a CALM-AF10 fusion in acute megakaryoblastic leukaemia

“…8 The breakpoints in CALM are towards the 3Ј end resulting in almost the entire length of CALM fused to various lengths of AF10 in CALM-AF10 fusion products. [9][10][11][12][13][14][15] Unlike the MLL-AF10 fusion, which appears to be associated with differentiated acute myeloid leukaemias (AML), mainly FAB M4 and M5, CALM-AF10 fusions are mainly identified in T cell acute lymphoblastic leukaemias (ALL) and undifferentiated AML (FAB M0 or M1). Recently it has also been reported in cases of FAB M5 AML.…”

Protean clinical manifestations in children with leukemias containing MLL-AF10 fusion

“…Recently, CALM-AF10 fusion has been reported in patients with T cell lymphoblastic lymphoma, AML-M4, AML-M5 and biphenotypic leukemia, in addition to those with T-ALL, AML-M0 and AML-M1. [16][17][18]31,32 One case of MLL-ABI1 fusion has been reported to date in a patient with AML-M4. 14 There is also a reported case of M5 AML, where splitting of AF10 resulted in both MLL-AF10 and AF10-HEAB fusions due to the insertion of 11q12 to 11q23.…”

“…25 These results were confirmed, and other cases were analyzed with nested RT-PCR assays as previously described. 16 Primer sequences are listed in Table 1. Nucleotide and exon numbers are per Chaplin et al 11 for AF10 and Nilson et al 26 for MLL.…”

“…15 Subsequently, CALM-AF10 fusion has been identified in both AML and ALL. [16][17][18][19] Because of this genetic heterogeneity, detailed molecular or FISH studies are required to define the molecular event present in patients with a t(10;11). Since most cases of MLL-AF10 fusion reported to date have occurred in patients with AML-M5, it has been suggested that MLL-AF10 and CALM-AF10 fusion are associated with distinct subsets of acute leukemia.…”