Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras .

Autor:	Chu SH; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Song EJ; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Chabon JR; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Minehart J; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Matovina CN; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Makofske JL; Department of Genetics, Harvard Medical School, Boston, MA., Frank ES; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Ross K; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Koche RP; Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY., Feng Z; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Xu H; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Krivtsov A; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA., Nussenzweig A; Laboratory of Genome Integrity, National Cancer Institute, National Institutes of Health, Rockville, MD; and., Armstrong SA; Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.; Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
Jazyk:	angličtina
Zdroj:	Blood advances [Blood Adv] 2018 Oct 09; Vol. 2 (19), pp. 2478-2490.
DOI:	10.1182/bloodadvances.2018021592
Abstrakt:	Infant B-cell acute lymphoblastic leukemias (B-ALLs) that harbor MLL-AF4 rearrangements are associated with a poor prognosis. One important obstacle to progress for this patient population is the lack of immunocompetent models that faithfully recapitulate the short latency and aggressiveness of this disease. Recent whole-genome sequencing of MLL-AF4 B-ALL samples revealed a high frequency of activating RAS mutations; however, single-agent targeting of downstream effectors of the RAS pathway in these mutated MLL- r B-ALLs has demonstrated limited and nondurable antileukemic effects. Here, we demonstrate that the expression of activating mutant N-Ras G12D 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-Ras G12D leukemia to small molecule inhibitors and found potent and synergistic preclinical efficacy of dual targeting of the Mek and Atr pathways in mouse- and patient-derived xenografts with both mutations in vivo, suggesting this combination as an attractive therapeutic opportunity that might be used to treat patients with these mutations. Our studies indicate that this mouse model of Mll-Af4/N-Ras B-ALL is a powerful tool to explore the molecular and genetic pathogenesis of this disease subtype, as well as a preclinical discovery platform for novel therapeutic strategies.
Databáze:	MEDLINE
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