Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells

Suzanne Schubbert, Kenneth Lieuw, Sara L. Rowe, Connie M. Lee, Xia Xin Li, Mignon L. Loh, D. Wade Clapp, Kevin M. Shannon

Research output: Contribution to journalArticle

117 Scopus citations

Abstract

PTPN11 encodes the protein tyrosine phosphatase SHP-2, which relays signals from growth factor receptors to Ras and other effectors. Germline PTPN11 mutations underlie about 50% of Noonan syndrome (NS), a developmental disorder that is associated with an elevated risk of juvenile myelomonocytic leukemia (JMML). Somatic PTPN11 mutations were recently identified in about 35% of patients with JMML; these mutations introduce amino acid substitutions that are largely distinct from those found in NS. We assessed the functional consequences of leukemia-associated PTPN11 mutations in murine hematopoietic cells. Expressing an E76K SHP-2 protein induced a hypersensitive pattern of granulocyte-macrophage colony-forming unit (CFU-GM) colony growth in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin 3 (IL-3) that was dependent on SHP-2 catalytic activity. E76K SHP-2 expression also enhanced the growth of immature progenitor cells with high replating potential, perturbed erythroid growth, and impaired normal differentiation in liquid cultures. In addition, leukemia-associated SHP-2 mutations conferred a stronger phenotype than a germline mutation found in patients with NS. Mutant SHP-2 proteins induce aberrant growth in multiple hematopoietic compartments, which supports a primary role of hyperactive Ras in the pathogenesis of JMML.

Original languageEnglish (US)
Pages (from-to)311-317
Number of pages7
JournalBlood
Volume106
Issue number1
DOIs
StatePublished - Jul 1 2005

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Fingerprint Dive into the research topics of 'Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells'. Together they form a unique fingerprint.

  • Cite this

    Schubbert, S., Lieuw, K., Rowe, S. L., Lee, C. M., Li, X. X., Loh, M. L., Clapp, D. W., & Shannon, K. M. (2005). Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. Blood, 106(1), 311-317. https://doi.org/10.1182/blood-2004-11-4207