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

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De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. / Hyrenius-Wittsten, Axel; Pilheden, Mattias; Sturesson, Helena; Hansson, Jenny; Walsh, Michael P.; Song, Guangchun; Kazi, Julhash U.; Liu, Jian; Ramakrishan, Ramprasad; Garcia-Ruiz, Cristian; Nance, Stephanie; Gupta, Pankaj; Zhang, Jinghui; Rönnstrand, Lars; Hultquist, Anne; Downing, James R.; Lindkvist-Petersson, Karin; Paulsson, Kajsa; Järås, Marcus; Gruber, Tanja A.; Ma, Jing; Hagström-Andersson, Anna K.

In: Nature Communications, Vol. 9, No. 1, 1770, 01.12.2018.

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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

VL - 9

JO - Nature Communications

T2 - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 1770

ER -