TY - JOUR
T1 - De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia
AU - Hyrenius-Wittsten, Axel
AU - Pilheden, Mattias
AU - Sturesson, Helena
AU - Hansson, Jenny
AU - Walsh, Michael P.
AU - Song, Guangchun
AU - Kazi, Julhash U.
AU - Liu, Jian
AU - Ramakrishan, Ramprasad
AU - Garcia-Ruiz, Cristian
AU - Nance, Stephanie
AU - Gupta, Pankaj
AU - Zhang, Jinghui
AU - Rönnstrand, Lars
AU - Hultquist, Anne
AU - Downing, James R.
AU - Lindkvist-Petersson, Karin
AU - Paulsson, Kajsa
AU - Järås, Marcus
AU - Gruber, Tanja A.
AU - Ma, Jing
AU - Hagström-Andersson, Anna K.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-018-04180-1
DO - 10.1038/s41467-018-04180-1
M3 - Article
C2 - 29720585
AN - SCOPUS:85046466943
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1770
ER -