Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia
Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama
Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama
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Research Article Hematology Oncology

Cooperative gene activation by AF4 and DOT1L drives MLL-rearranged leukemia

Abstract

The eleven-nineteen leukemia (ENL) protein family, composed of ENL and AF9, is a common component of 3 transcriptional modulators: AF4–ENL–P-TEFb complex (AEP), DOT1L-AF10-ENL complex (referred to as the DOT1L complex) and polycomb-repressive complex 1 (PRC1). Each complex associates with chromatin via distinct mechanisms, conferring different transcriptional properties including activation, maintenance, and repression. The mixed-lineage leukemia (MLL) gene often fuses with ENL and AF10 family genes in leukemia. However, the functional interrelationship among those 3 complexes in leukemic transformation remains largely elusive. Here, we have shown that MLL-ENL and MLL-AF10 constitutively activate transcription by aberrantly inducing both AEP-dependent transcriptional activation and DOT1L-dependent transcriptional maintenance, mostly in the absence of PRC1, to fully transform hematopoietic progenitors. These results reveal a cooperative transcriptional activation mechanism of AEP and DOT1L and suggest a molecular rationale for the simultaneous inhibition of the MLL fusion–AF4 complex and DOT1L for more effective treatment of MLL-rearranged leukemia.

Authors

Hiroshi Okuda, Boban Stanojevic, Akinori Kanai, Takeshi Kawamura, Satoshi Takahashi, Hirotaka Matsui, Akifumi Takaori-Kondo, Akihiko Yokoyama

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Figure 6

Recruitment of both AF4 and DOT1L activities is required for MLL fusion–dependent leukemogenesis.

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Recruitment of both AF4 and DOT1L activities is required for MLL fusion–...
(A) Cooperative transformation by recruitment of AF4 and DOT1L activities. Doubly transduced cells were selected in the first round. Hoxa9 expression and colony-forming activity were analyzed as in Figure 4D. **P ≤ 0.01, by ordinary 1-way ANOVA, comparing the indicated sample pairs. neo, neomycin. (B) Leukemogenic potential of various constructs in vivo. Survival of mice transplanted with hematopoietic progenitors transduced with the indicated transgenes. n values indicate the number of mice analyzed.