De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia

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Bibtex

@article{0c95edb585da4161b710e266101b8127,
title = "De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia",
abstract = "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.",
author = "Axel Hyrenius-Wittsten and Mattias Pilheden and Helena Sturesson and Jenny Hansson and Walsh, {Michael P.} and Guangchun Song and Kazi, {Julhash U.} and Jian Liu and Ramprasad Ramakrishan and Cristian Garcia-Ruiz and Stephanie Nance and Pankaj Gupta and Jinghui Zhang and Lars R{\"o}nnstrand and Anne Hultquist and Downing, {James R.} and Karin Lindkvist-Petersson and Kajsa Paulsson and Marcus J{\"a}r{\aa}s and Gruber, {Tanja A.} and Jing Ma and Hagstr{\"o}m-Andersson, {Anna K.}",
year = "2018",
month = "12",
day = "1",
doi = "10.1038/s41467-018-04180-1",
language = "English",
volume = "9",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
number = "1",

}