Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-04180-1
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Funding
- Swedish Childhood Cancer Foundation
- Swedish Cancer Society
- The Swedish Research Council
- The Knut and Alice Wallenberg Foundation
- BioCARE
- The Gunnar Nilsson Cancer Foundation
- Ellen Bachrachs Memorial Foundation
- The Craaford Foundation
- The Per-Eric and Ulla Schyberg Foundation
- The Nilsson-Ehle Donations
- The Wiberg Foundation
- Governmental Funding of Clinical Research within the National Health Service
- Swedish National Infrastructure for Biological Mass Spectrometry (BioMS)
- The Georg Danielsson Foundation for Hematopoietic Disease
- NATIONAL CANCER INSTITUTE [P30CA021765] Funding Source: NIH RePORTER
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Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3(ITD), FLT3(N676K), and NRAS(G12D) accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3(N676K) mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the Kras(G12D) locus, consistent with a strong selective advantage of additional Kras(G12D). KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver.
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