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.

Transcription Factors Activate Genes through the Phase-Separation Capacity of Their Activation Domains

“…These abnormal gene products often fuse a DNA-or chromatin-binding domain to a wide array of partners, many of which are IDRs. For example, MLL may be fused to 80 different partner genes in AML (Winters and Bernt, 2017), the EWS-FLI rearrangement in Ewing’s Sarcoma causes malignant transformation by recruitment of a disordered domain to oncogenes (Boulay et al, 2017; Chong et al, 2017), and the disordered phase-separating protein FUS is found fused to a DBD in certain sarcomas (Crozat et al, 1993; Patel et al, 2015). Phase separation provides a mechanism by which such gene products result in aberrant gene expression programs; by recruiting a disordered protein to the chromatin, diverse coactivators may form phase-separated condensates to drive oncogene expression.…”

The Histone Methyltransferase MLL1 Directs Macrophage-Mediated Inflammation in Wound Healing and Is Altered in a Murine Model of Obesity and Type 2 Diabetes

“…This early introduction of MLL1 in wound macrophages may prevent the subsequent late overexpression of MLL1 that contributes to increased inflammation in diabetic wounds. The second and most translatable strategy would be MLL1 small-molecule inhibitors that are currently approved by the U.S. Food and Drug Administration for use in cancer (35,36). MLL1 inhibitors are attractive for use in wounds because they can be locally administered, negating many of the toxic effects of systemic administration (36).…”

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells

“…Literature data suggests roughly about 10% of acute leukemia (AL) patients harbor chromosomal rearrangements involving the gene MLL (also known as KMT2A ). Acute myeloid leukemia (AML) with such MLL‐rearrangements ( MLLr ) mainly manifests in young‐to‐middle‐aged adults whereas acute lymphoblastic leukemia (ALL) with MLL r occurs predominantly in patients younger than 1 year at diagnosis . AML with MLL fusion to MLLT3 via the balanced translocation t(9;11)(p22;q23) predicts intermediate prognosis whereas fusion to other partners carries a rather adverse prognosis .…”