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Inhibition of MEK and ATR induces synergistic killing of a Mll-Af4 B-ALL model harboring activated Ras mutation

ABSTRACT: Infant B-acute lymphoblastic leukemias (B-ALL) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of models that faithfully recapitulate the short latency and aggressiveness of this disease. While current mouse models of Mll-Af4 can generate acute leukemia, not all are lymphoid, and the long latency to disease does not reflect what is seen in patients. Recent whole genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of mutations in proto-oncogenes involved in signaling pathways. Here, we demonstrate that the expression of activating mutant N-RasG12D cooperates with Mll-Af4 to generate a highly aggressive, serially transplantable B-ALL in mice. We used our novel mouse model to test the sensitivity of Mll-Af4/N-RasG12D leukemia to small molecule inhibitors, and found that dual targeting of the downstream effectors of Ras and the DNA damage response pathway through ATR inhibition induced long-term durable responses in both mouse and patient derived xenografts with both mutations in vivo. Our studies suggest that this mouse model of Mll-Af4/N-Ras B-ALL is not only a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, but also is an important preclinical discovery platform for novel therapeutics that might be used to treat patients with this disease.

ORGANISM(S): Mus musculus

PROVIDER: GSE89560 | GEO | 2018/11/28

REPOSITORIES: GEO

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