MLL2, but not MLL1, plays a major role to sustain leukemia survival [array]

The MLL1 histone methyltransferase gene undergoes many distinct chromosomal rearrangements to yield poor-prognosis leukemia. The remaining wild-type allele is most commonly, but not always, retained. To what extent the wild-type allele contributes to leukemogenesis is unclear. Here we show using rigorous, independent animal models that endogenous MLL1 is dispensable for MLL-rearranged leukemia. Potential redundancy was addressed by co-deleting the closest paralog, Mll2. Surprisingly, Mll2 deletion alone had a significant impact on survival of MLL-AF9-transformed cells and additional Mll1 loss further reduced viability and proliferation. We show that MLL1/MLL2 collaboration is not through redundancy but regulation of distinct pathways. These findings highlight the relevance of MLL2 as a drug target in MLL-rearranged leukemia and suggest its broader significance in AML. We used microarray to investigate the effect of Mll1 deletion on gene expression in LSC-enriched MLL-AF9 leukemia cells. Primary MLL-AF9 leukemia mice transformed from Lin-/Sca1+/c-Kit+ (LSK) cells with the genotype of Cre+;Mll1F/+ or Cre+;Mll1F/F were injected with two doses of tamoxifen (TAM) to induce Mll1 deletion. Three days after the last TAM injection, YFP+/Lin-/c-Kit+ leukemia cells were sorted for RNA extraction and microarray.