| First Author | Hyrenius-Wittsten A | Year | 2018 |
| Journal | Nat Commun | Volume | 9 |
| Issue | 1 | Pages | 1770 |
| PubMed ID | 29720585 | Mgi Jnum | J:262915 |
| Mgi Id | MGI:6161023 | Doi | 10.1038/s41467-018-04180-1 |
| Citation | Hyrenius-Wittsten A, et al. (2018) De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. Nat Commun 9(1):1770 |
| abstractText | 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. |
