Abstract
The mixed-lineage leukemia 1 (MLL1) gene (now renamed Lysine [K]-specific MethylTransferase 2A or KMT2A) on chromosome 11q23 is disrupted in a unique group of acute leukemias. More than 80 different partner genes in these fusions have been described, although the majority of leukemias result from MLL1 fusions with one of about six common partner genes. Approximately 10% of all leukemias harbor MLL1 translocations. Of these, two patient populations comprise the majority of cases: patients younger than 1 year of age at diagnosis (primarily acute lymphoblastic leukemias) and young- to-middle-aged adults (primarily acute myeloid leukemias). A much rarer subgroup of patients with MLL1 rearrangements develop leukemia that is attributable to prior treatment with certain chemotherapeutic agents—so-called therapy-related leukemias. In general, outcomes for all of these patients remain poor when compared to patients with non-MLL1 rearranged leukemias. In this review, we will discuss the normal biological roles of MLL1 and its fusion partners, how these roles are hypothesized to be dysregulated in the context of MLL1 rearrangements, and the clinical manifestations of this group of leukemias. We will go on to discuss the progress in clinical management and promising new avenues of research, which may lead to more effective targeted therapies for affected patients.
Highlights
Division of Pediatric Hematology/Oncology/BMT, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora, CO, USA
The N-terminal portion of the protein contains a domain for binding Menin, a protein that serves as a link between mixed-lineage leukemia 1 (MLL1) and the chromatin-binding protein lens epithelium-derived growth factor (LEDGF)
Hox genes are expressed in Mll1−/− embryos before the E9.0 stage, their expression is not maintained at later time points in the absence of Mll1 [34]. These findings indicate that Mll1 is required for the maintenance, and not the initiation, of Hox gene expression
Summary
The cooperation of most major MLL1 fusion partners in a single elongation regulatory complex, termed “super elongation complex” (SEC), “AF4/ENL family protein complex,” or “ENLassociated protein complex”, offered an elegant explanation for the large number of different partners: translocation of any of the members of a large complex containing AF10, AF17, AF9, ENL, ELL, AF4, AF5, pTEFb, and DOT1L would cause aberrant transcriptional elongation and similar phenotypes. It seems safe to say that dysregulated expression of the HOX developmental regulators and their cofactor MEIS1 contributes critically to the stem cell-like characteristics of MLL-r leukemias and confers or maintains on these cells self-renewal properties, growth, and survival advantages that promote their oncogenic potential. These stem cell-like properties—which may in part depend on the developmental stage at which the leukemia arose (stem cell vs early progenitor)—have been proposed to contribute to the high level of resistance to programmed cell death frequently observed in the clinic [86,87,88,89,90,91]. Frequent dysregulation of prosurvival pathways such as BCL-2, which counteracts the intrinsic mitochondria-mediated apoptotic pathway, may contribute to the therapeutic difficulties many of these leukemias pose in the clinical setting [89, 92]
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