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. GruberJing Ma, Anna K. Hagström-Andersson

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

Sammanfattning

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.

Originalspråkengelska
Artikelnummer1770
TidskriftNature Communications
Volym9
Nummer1
DOI
StatusPublished - 2018 dec. 1

Ämnesklassifikation (UKÄ)

  • Hematologi
  • Medicinsk genetik

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