A novel chromosomal inversion at 11q23 in infant acute myeloid leukemia fuses MLL to CALM, a gene that encodes a clathrin assembly protein

Abstract

Rearrangements involving the MLL gene at chromosome band 11q23 are common in infant acute myeloid leukemias (AMLs). We recently encountered an infant patient with rapidly progressive AML whose leukemic cells harbored a previously undescribed MLL rearrangement involving an inversion of 11q [inv(11)(q14q23)]. We used panhandle PCR to determine that this rearrangement juxtaposed the MLL (Mixed-Lineage Leukemia) gene to the CALM (Clathrin Assembly Lymphoid Myeloid leukemia) gene at 11q14-q21. The CALM protein participates in recruitment of clathrin to internal membrane surfaces, thereby regulating vesicle formation in both endocytosis and intracellular protein transport. Intriguingly, CALM has been identified in other cases of AML as a translocation partner for the AF10 gene, which has independently been found to be an MLL partner in AML. We identified the MLL-CALM fusion transcript (but not the reciprocal CALM-MLL transcript) in leukemia cell RNA by RT-PCR. The predicted 1803 amino acid MLL-CALM fusion protein includes amino-terminal MLL domains involved in transcriptional repression, and carboxy-terminal CALM-derived clathrin-binding domains. The genomic breakpoint in MLL is in the 7th intron (within the breakpoint cluster region); the corresponding CALM breakpoint is in the 7th CALM intron. In contrast, breakpoints in CALM-AF10 translocations lie in the 17th-19th CALM introns (30 kb downstream); also, in these translocations, CALM provides the 5' end of the fusion transcript. Together with its previously recognized association with AF10 in AML, the identification of CALM as an MLL fusion partner suggests that interference with clathrin-mediated trafficking pathways may be an underappreciated mechanism in leukemogenesis.

The role of CALM–AF10 gene fusion in acute leukemia

“…24 A single case report described an MLL-CALM fusion in a 12-week-old Caucasian female who presented with rapidly progressive acute myeloid leukemia (AML). 25 In this study, the authors used panhandle PCR to determine that MLL was fused to CALM at 11q14-q21. By assaying RNA from the patient's leukemic cells, fusion transcripts were identified.…”

CALM-AF10+ T-ALL expression profiles are characterized by overexpression of HOXA and BMI1 oncogenes

“…CALM has also been shown to be fused to MLL, in a unique case of t(10;11)(p13;q23) observed in an infant AML. 6 AF10 was first identified as a fusion partner of MLL in AMLs. 7,8 AF10 is expressed ubiquitously and codes for a protein of 1027 aa.…”

Long-term follow-up of a patient with idiopathic myelofibrosis associated with chromosome 11 and 13 abnormalities

“…A definite role of CALM in endocytic vesicle formation has been demonstrated by the ability of over-expressed CALM to interfere with endocytosis of receptors for both transferrin and epidermal growth factor [15]. Wechsler et al reported MLL-CALM fusion transcript involving an inversion 11q [inv (11)(q14q23)] associated with infant AML leukemogenesis [16]. Chromosomal abnormality of 11, del (11)(11q14q23), was continuously detected every time we examined the patient.…”