Acute Myeloid Leukemias with Alterations of Lysine Methyltransferase 2A (KMT2A): Recent Therapeutic Developments

Chromosomal rearrangements involving the Lysine Methyl Transferase 2 A (KMT2A) define a genetically distinct subset of acute myeloid leukemia (AML) in about 10% of cases in adult patients; the frequency of KMT2A-r is higher in pediatric AML. Translocations involving the KMT2A-locus at chromosome 11q23 result in the formation of a chimeric oncogene partner, where the N-terminal part of KMT2A is fused to a variety of translocation partners. The leukemogenic activity of KMT2A-fusion partners is related to their capacity to hyperactivate the expression of HOX-A and MEIS1 target genes which stimulate the proliferation and expansion of hematopoietic stem cells. The oncogenic activity of KMT2A fusion proteins requires the interaction with Menin and this interaction can be targeted pharmacologically by small molecules acting as potent and selective Menin inhibitors. The presence of KMT2A-r is associated with adverse outcomes in AML patients. In the present review article, we summarize our current understanding about the biology of KMT2A-r in AML development and the recent consistent progresses made in the treatment of KMT2A-r AML through new chemotherapy regimens and targeted therapy using Menin inhibitors. These studies have led to consistent improvements in the outcomes of KMT2A-r AML patients. However, the prognosis of older KMT2A-r AML patients remains poor and could be improved by drug combination studies including Menin inhibitors. Many encouraging observations derived from ongoing clinical trials with Menin inhibitors need to be confirmed through randomized clinical trials.