De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A -rearranged leukemia
2018
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.
Keywords:
- Correction
- Source
- Cite
- Save
- Machine Reading By IdeaReader
70
References
25
Citations
NaN
KQI