MLL2 Promotes Cell Survival in MLL1-Rearranged Acute Myeloid Leukemia

Chromosomal rearrangements in the histone methyltransferase gene MLL1 are associated with a poor prognosis in acute myeloid leukemia (AML). In most cases of MLL-rearranged leukemia, the second wild-type allele of MLL1 is retained, and it has been assumed that the remaining endogenous MLL1 is responsible for maintaining the H3K4 methylation status. Chen and colleagues sought to fully characterize the role of MLL1 in MLL-rearranged leukemia. Unexpectedly, Mll1 deletion did not suppress MLL-AF9 or MLL-AF6–driven leukemia in vivo. Further, Mll1 deletion did not suppress the growth of leukemic stem cells. In contrast, the essential MLL cofactor MEN1 was required for leukemia maintenance. Although MLL1 was dispensable in MLL-rearranged leukemia, concomitant loss of the closely related MLL2 protein suppressed the growth of MLL-AF9 leukemia cells in vitro and delayed leukemogenesis in vivo. RNA sequencing showed that although Mll1 deletion alone affected expression of few genes, Mll2 deletion altered expression of 171 genes, and combined deletion deregulated 444 genes. Codeletion of Mll1 and Mll2 resulted in upregulation of genes involved in cell death and apoptosis, but did not affect expression of MLL-AF9 target genes. Chromatin immunoprecipitation sequencing found that MLL2 loss resulted in a global reduction in H3K4me2/me3, which was not exacerbated by MLL1 loss. Thus, MLL1 loss alters expression of MLL2 target genes through an alternative mechanism. Moreover, codeletion of Mll1 and Mll2 reduced expression of genes in the NF-κB, integrin β3, and IL3 survival pathways to promote leukemia cell viability. In addition to demonstrating that MLL1 and MLL2 have nonredundant functions in AML, the finding that MLL2 promotes survival of MLL-rearranged leukemia cells suggests that it may be a potential therapeutic target.

Chen Y, Anastassiadis K, Kranz A, Stewart AF, Arndt K, Waskow C, et al. MLL2, not MLL1, plays a major role in sustaining MLL-rearranged acute myeloid leukemia. Cancer Cell 2017;31:755–70.

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