MLL-Rearranged Leukemias-An Update on Science and Clinical Approaches

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.

Keywords: HSCT; chemotherapy; epigenetics; infant leukemia; mixed lineage leukemia; targeted inhibitor.

Figure 1

The structure of mixed-lineage leukemia (MLL) and normal vs aberrant MLL complexes. (A) The structure of the wild-type MLL protein, emphasizing the functional domains. MBD, Menin-binding domain; AT, AT hooks; SNL, speckled nuclear localization domains; RD, repression domains (black box in first RD represents the CXXC domain); BCR, breakpoint cluster region; PHD, PHD fingers; BD, bromodomain. CS1 and CS2 are the taspase-1 cleavage sites, and FYRN and FYRC are the domains whereby MLL-N and MLL-C interact after cleavage. TAD, transactivation domain; SET, H3K4 histone methyltransferase domain. (B) MLL fusion proteins are caused by chromosomal rearrangements leading to in-frame fusions between N-terminal MLL (to the BCR) and any of 80 different fusion partners. PHD domains, transactivation domains, and the SET domain are lost. (C) MLL-interacting proteins. Proteins involved in repressive functions of MLL are grouped above the MLL protein (regulated by CYP33), whereas proteins involved in activation of MLL-dependent transcription are grouped below the MLL protein schematic.

Figure 2

Putative complexes between mixed-lineage leukemia (MLL) fusions and nuclear proteins involved in histone modifications and transcriptional elongation. MEN1, Menin; FP, fusion partner. AF10, AF17, AF9, ENL, ELL, AF4, and AF5 have all been reported as MLL1 fusion partner, as well as interaction partner with each other, DOT1L, and pTEFb. However, DOT1L and pTEFb most likely do not reside within one large complex (73, 74). Red stars depict opportunities for targeted inhibition—Protein–protein: (1) Menin-MLL1 interaction. Chromatin: (2) LEDGF—H3K36me2 interaction (blocking reader domain or ASH1L). (3) AF10—unmodified H3K27 interaction (blocking reader domain or demethylases?). (4) DOT1L—placement of H3K79me2/3 (blocking methyltransferase domain). Pol II phosphorylation: (5) Inhibition of pTEFb. Downstream targets: (6) FLT3.

Figure 3

Mixed-lineage leukemia (MLL)-rearranged leukemias involve fusions of 11q23 with 1 of more than 80 different partner genes. Six or seven fusion partners are responsible for the majority of cases. The pie chart illustrates the relative frequencies of the different fusion partners in acute lymphoblastic leukemia (ALL) and acute myeloid leukemias (AML), respectively. Numbers are adapted from the published data by Meyer et al. (29). The bottom half of the figure shows the breakdown of the relative frequencies of MLL fusion partners based on the leukemia type (ALL vs AML) and age group.