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

Axel Hyrenius-Wittsten, Mattias Pilheden, Helena Sturesson, Jenny Hansson, Michael P. Walsh, Guangchun Song, Julhash U. Kazi, Jian Liu, Ramprasad Ramakrishan, Cristian Garcia-Ruiz, Stephanie Nance, Pankaj Gupta, Jinghui Zhang, Lars Rönnstrand, Anne Hultquist, James R. Downing, Karin Lindkvist-Petersson, Kajsa Paulsson, Marcus Järås, Tanja A. Gruber, Jing Ma and Anna K. Hagström-Andersson ()
Additional contact information
Axel Hyrenius-Wittsten: Lund University
Mattias Pilheden: Lund University
Helena Sturesson: Lund University
Jenny Hansson: Lund University
Michael P. Walsh: St. Jude Children´s Research Hospital
Guangchun Song: St. Jude Children´s Research Hospital
Julhash U. Kazi: Lund University
Jian Liu: Lund University
Ramprasad Ramakrishan: Lund University
Cristian Garcia-Ruiz: Lund University
Stephanie Nance: St. Jude Children´s Research Hospital
Pankaj Gupta: St. Jude Children´s Research Hospital
Jinghui Zhang: St. Jude Children´s Research Hospital
Lars Rönnstrand: Lund University
Anne Hultquist: Lund University
James R. Downing: St. Jude Children´s Research Hospital
Karin Lindkvist-Petersson: Medical Structural Biology, Department of Experimental Medical Science, 221 84 Lund University
Kajsa Paulsson: Lund University
Marcus Järås: Lund University
Tanja A. Gruber: St. Jude Children´s Research Hospital
Jing Ma: St. Jude Children´s Research Hospital
Anna K. Hagström-Andersson: Lund University

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-04180-1

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