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Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia.

Publication ,  Journal Article
Wang, J; Liu, Y; Li, Z; Du, J; Ryu, M-J; Taylor, PR; Fleming, MD; Young, KH; Pitot, H; Zhang, J
Published in: Blood
December 23, 2010

Oncogenic NRAS mutations are frequently identified in myeloid diseases involving monocyte lineage. However, its role in the genesis of these diseases remains elusive. We report a mouse bone marrow transplantation model harboring an oncogenic G12D mutation in the Nras locus. Approximately 95% of recipient mice develop a myeloproliferative disease resembling the myeloproliferative variant of chronic myelomonocytic leukemia (CMML), with a prolonged latency and acquisition of multiple genetic alterations, including uniparental disomy of oncogenic Nras allele. Based on single-cell profiling of phospho-proteins, a novel population of CMML cells is identified to display aberrant granulocyte-macrophage colony stimulating factor (GM-CSF) signaling in both the extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription 5 (Stat5) pathways. This abnormal signaling is acquired during CMML development. Further study suggests that aberrant Ras/ERK signaling leads to expansion of granulocytic/monocytic precursors, which are highly responsive to GM-CSF. Hyperactivation of Stat5 in CMML cells is mainly through expansion of these precursors rather than up-regulation of surface expression of GM-CSF receptors. Our results provide insights into the aberrant cytokine signaling in oncogenic NRAS-associated myeloid diseases.

Duke Scholars

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 23, 2010

Volume

116

Issue

26

Start / End Page

5991 / 6002

Location

United States

Related Subject Headings

  • Survival Rate
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • RNA, Messenger
  • Mutation
  • Monocytes
  • Mice, Inbred C57BL
  • Mice
  • Leukemia, Myelomonocytic, Chronic
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wang, J., Liu, Y., Li, Z., Du, J., Ryu, M.-J., Taylor, P. R., … Zhang, J. (2010). Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood, 116(26), 5991–6002. https://doi.org/10.1182/blood-2010-04-281527
Wang, Jinyong, Yangang Liu, Zeyang Li, Juan Du, Myung-Jeom Ryu, Philip R. Taylor, Mark D. Fleming, Ken H. Young, Henry Pitot, and Jing Zhang. “Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia.Blood 116, no. 26 (December 23, 2010): 5991–6002. https://doi.org/10.1182/blood-2010-04-281527.
Wang, Jinyong, et al. “Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia.Blood, vol. 116, no. 26, Dec. 2010, pp. 5991–6002. Pubmed, doi:10.1182/blood-2010-04-281527.
Wang J, Liu Y, Li Z, Du J, Ryu M-J, Taylor PR, Fleming MD, Young KH, Pitot H, Zhang J. Endogenous oncogenic Nras mutation promotes aberrant GM-CSF signaling in granulocytic/monocytic precursors in a murine model of chronic myelomonocytic leukemia. Blood. 2010 Dec 23;116(26):5991–6002.

Published In

Blood

DOI

EISSN

1528-0020

Publication Date

December 23, 2010

Volume

116

Issue

26

Start / End Page

5991 / 6002

Location

United States

Related Subject Headings

  • Survival Rate
  • Signal Transduction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Receptors, Granulocyte-Macrophage Colony-Stimulating Factor
  • RNA, Messenger
  • Mutation
  • Monocytes
  • Mice, Inbred C57BL
  • Mice
  • Leukemia, Myelomonocytic, Chronic