MLL2, Not MLL1, Plays a Major Role in Sustaining MLL-Rearranged Acute Myeloid Leukemia

Publication date: 12 June 2017
Source:Cancer Cell, Volume 31, Issue 6
Author(s): Yufei Chen, Konstantinos Anastassiadis, Andrea Kranz, A. Francis Stewart, Kathrin Arndt, Claudia Waskow, Akihiko Yokoyama, Kenneth Jones, Tobias Neff, Yoo Lee, Patricia Ernst
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.

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Teaser

Chen et al. report that wild-type MLL1 is dispensable for MLL fusion leukemia, but instead loss of MLL2 reduces the survival of leukemia cells from human cell lines and in a mouse model of MLL-AF9 AML. Combined loss of MLL1 and MLL2 further reduces leukemia cell viability.


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