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

Hyrenius-Wittsten, Axel LU ; Pilheden, Mattias LU ; Sturesson, Helena LU ; Hansson, Jenny LU ; Walsh, Michael P.; Song, Guangchun; Kazi, Julhash U. LU ; Liu, Jian; Ramakrishan, Ramprasad LU and Garcia-Ruiz, Cristian LU , et al. (2018) In Nature Communications 9(1).
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... (More)

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.

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Nature Communications
volume
9
issue
1
publisher
Nature Publishing Group
external identifiers
  • scopus:85046466943
ISSN
2041-1723
DOI
10.1038/s41467-018-04180-1
language
English
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yes
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0c95edb5-85da-4161-b710-e266101b8127
date added to LUP
2018-05-15 08:55:46
date last changed
2018-11-21 21:39:48
@article{0c95edb5-85da-4161-b710-e266101b8127,
  abstract     = {<p>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 <sup>ITD</sup>, FLT3 <sup>N676K</sup>, and NRAS <sup>G12D</sup> accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 <sup>N676K</sup> 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 <sup>G12D</sup> locus, consistent with a strong selective advantage of additional Kras <sup>G12D</sup> . 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.</p>},
  articleno    = {1770},
  author       = {Hyrenius-Wittsten, Axel and Pilheden, Mattias and Sturesson, Helena and Hansson, Jenny and Walsh, Michael P. and Song, Guangchun and Kazi, Julhash U. and Liu, Jian and Ramakrishan, Ramprasad and Garcia-Ruiz, Cristian and Nance, Stephanie and Gupta, Pankaj and Zhang, Jinghui and Rönnstrand, Lars and Hultquist, Anne and Downing, James R. and Lindkvist-Petersson, Karin and Paulsson, Kajsa and Järås, Marcus and Gruber, Tanja A. and Ma, Jing and Hagström-Andersson, Anna K.},
  issn         = {2041-1723},
  language     = {eng},
  month        = {12},
  number       = {1},
  publisher    = {Nature Publishing Group},
  series       = {Nature Communications},
  title        = {De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia},
  url          = {http://dx.doi.org/10.1038/s41467-018-04180-1},
  volume       = {9},
  year         = {2018},
}