Inv(11)(q21q23) Fuses MLL to the NOTCH Co-Activator Mastermind-Like 2 in Secondary T Cell Acute Lymphoblastic Leukemia.

Development of a secondary leukemia after chemotherapeutic treatment for childhood acute leukemia is associated with rearrangements of the MLL gene on chromosome 11q23 and characteristically results in acute myeloid leukemia (AML). We identified the NOTCH co-activator Mastermind-like 2 as MLL fusion partner in two cases of pediatric secondary leukemia. The MLL-MAML2 fusion results from a cryptic inv(11)(q21q23) only detectable by interphase fluorescence in situ hybridization with an MLL split signal probe. With a latency of twenty months and five years after initial diagnosis for MLL negative AML and precursor B acute lymphoblastic leukemia (ALL), respectively, both patients developed a therapy-related T-cell acute lymphoblastic leukemia.

MAML2 is the first MLL fusion partner involved in human Notch-signaling and was only recently identified as recurrent translocation fusion partner in a subset of salivary gland tumors. The genomic MLL breakpoint shows similar localization and sequence features described for etoposide induced treatment-related AML. MLL-MAML2 positive cells were detectable up to two years prior to clinical apparent secondary leukemia in one case. The discrepant dynamics of clone expansion quantified by either the genomic fusion sequence or Ig/TCR gene rearrangements as clone specific markers suggests a selection process within the inversion positive population and the need for additional mutation events to promote overt leukemic disease. Whole genome expression profiles demonstrated differential expression of both typical MLL and NOTCH downstream genes, which suggests a modulatory role of the MAML2 transcriptional activation domain in MLL leukemogenesis and lineage assignment induced by the MLL-MAML2 fusion protein.

MSM21620813

WSF3401600.