Identification of a novel fusion gene MLL‐MAML2 in secondary acute myelogenous leukemia and myelodysplastic syndrome with inv(11)(q21q23)

Abstract

We have identified a novel fusion partner of MLL, namely the mastermind like 2 (MAML2 gene), in secondary acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with inv(11)(q21q23). RT-PCR and sequencing revealed that exon 7 of MLL was fused to exon 2 of MAML2 in the AML and MDS cells. The inv(11)(q21q23) results in the creation of a chimeric RNA encoding a putative fusion protein containing 1,408 amino acids from the NH2-terminal part of MLL and 952 amino acids from the COOH-terminal part of MAML2. The NH2-terminal part of MAML2, a basic domain including a binding site of the intracellular domain of NOTCH, was deleted in MLL-MAML2. MLL-MAML2 in secondary AML/MDS and MECT1-MAML2 in mucoepithelioid carcinoma, benign Wartin's tumor, and clear cell hidradenoma consist of the same COOH-terminal part of MAML2. A luciferase assay revealed that MLL-MAML2 suppressed HES1 promoter activation by the NOTCH1 intracellular domain. MAML2 involving a chimeric gene might contribute to carcinogenesis in multiple neoplasms by the disruption of NOTCH signaling.

Inv(11)(q21q23) fuses MLL to the Notch co-activator mastermind-like 2 in secondary T-cell acute lymphoblastic leukemia

“…2 Fusions between MLL and MAML2 have recently been reported for two adult leukemia patients with secondary AML and myelodysplastic syndrome. 3 Here, we describe the development of secondary T-cell acute lymphoblastic leukemia (T-ALL) in two adolescent leukemia patients. Therapy-related ALL (t-ALL) was diagnosed in a 13-year-old boy 20 months after cessation of treatment for primary AML FAB-M4 Eo.…”

Mastermind-Like 3 Controls Proliferation and Differentiation in Neuroblastoma

“…This translocation has been recurrently found in salivary gland tumors, mucoepidermoid carcinoma, Warthin tumor, and clear cell hidradenoma of the skin. In AML and MDS patients, MLL-MAML2 fusions have been described (39). This fusion disrupts NOTCH signaling and that possibly contributes to carcinogenesis in these malignancies.…”

Covert preleukemia driven by MLL gene fusion

“…In these reports, no data were provided on additional genetic abnormalities that might have contributed to leukemogenesis (Leblanc et al, 1994;Megonigal et al, 2000;Blanco et al, 2001;Metzler et al, 2004;Ng et al, 2004;Takei et al, 2006;Nemoto et al, 2007;Metzler et al, 2008). In the case of secondary myelodysplastic syndrome (MDS) with MLL/FRYL fusion (Robinson et al, 2008), a subclonal presence of t(2;9) was detected in 0-6/20 mitoses in some samples preceding the secondary MDS and loss of chromosome 16 and add (18q) were shown 3 months before the evident secondary MDS diagnosis in 4 out of 17 t(4;11) positive cells.…”

“…In these cases the MLL positive cells characteristic for the secondary malignancy were described as progressively expanding clone finally prevailing over the normal hematopoiesis causing clinical symptoms of leukemia. On the contrary, Japanese group detected an inv(11)(q21;q23) with MLL/MAML2 fusion almost 6 years before the secondary AML onset (Takei et al, 2006;Nemoto et al, 2007). Two cases describing treatment related MLL translocation were published recently.…”

“…The majority of secondary or treatment related leukemias with MLL gene rearrangements are also characterized by a relatively short latency (Felix, 1998). On the other hand, in a few cases of secondary hematological malignancies with MLL gene fusions, it has been possible to backtrack the appearance of the MLL rearrangement to several months (up to more than 6 years) prior to diagnosis of secondary leukemia (Leblanc et al, 1994;Megonigal et al, 2000;Blanco et al, 2001;Metzler et al, 2004;Ng et al, 2004;Takei et al, 2006;Nemoto et al, 2007;Metzler et al, 2008;Robinson et al, 2008) (see Table 1). We report here a case of secondary, B-lineage acute lymphoblastic leukemia (ALL) with MLL/ FOXO3A fusion gene.…”