Inhibition of MEK and ATR is effective in a B-cell acute lymphoblastic leukemia model driven by Mll-Af4 and activated Ras.
S Haihua ChuEvelyn J SongJonathan R ChabonJanna MinehartChloe N MatovinaJessica L MakofskeElizabeth S FrankKenneth N RossRichard P KocheZhaohui FengHaiming XuAndrei KrivtsovAndre NussenzweigScott A ArmstrongPublished in: Blood advances (2019)
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.
Keyphrases
- wild type
- acute myeloid leukemia
- poor prognosis
- atrial fibrillation
- small molecule
- protein protein
- mouse model
- high frequency
- acute lymphoblastic leukemia
- allogeneic hematopoietic stem cell transplantation
- long non coding rna
- signaling pathway
- cancer therapy
- transcranial magnetic stimulation
- liver failure
- gene expression
- dna methylation
- drug delivery
- metabolic syndrome
- single molecule
- skeletal muscle
- dna damage response
- copy number
- genome wide
- hepatitis b virus
- single cell
- mesenchymal stem cells
- respiratory failure
- extracorporeal membrane oxygenation
- aortic dissection