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

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

Research output: Contribution to journalArticle

115 Citations (Scopus)

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
Externally publishedYes

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Functional analysis
Juvenile Myelomonocytic Leukemia
Noonan Syndrome
Leukemia
Granulocyte-Macrophage Progenitor Cells
Mutation
Germ-Line Mutation
Growth
Non-Receptor Type 11 Protein Tyrosine Phosphatase
Growth Factor Receptors
Macrophages
Interleukin-3
Amino Acid Substitution
Granulocyte-Macrophage Colony-Stimulating Factor
Catalyst activity
Proteins
Substitution reactions
Stem Cells
Phenotype
Amino Acids

ASJC Scopus subject areas

  • Hematology

Cite this

Schubbert, S., Lieuw, K., Rowe, S. L., Lee, C. M., Li, X., Loh, M. L., ... 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

Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. / Schubbert, Suzanne; Lieuw, Kenneth; Rowe, Sara L.; Lee, Connie M.; Li, XiaXin; Loh, Mignon L.; Clapp, D.; Shannon, Kevin M.

In: Blood, Vol. 106, No. 1, 01.07.2005, p. 311-317.

Research output: Contribution to journalArticle

Schubbert, S, Lieuw, K, Rowe, SL, Lee, CM, Li, X, Loh, ML, Clapp, D & Shannon, KM 2005, 'Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells', Blood, vol. 106, no. 1, pp. 311-317. https://doi.org/10.1182/blood-2004-11-4207
Schubbert, Suzanne ; Lieuw, Kenneth ; Rowe, Sara L. ; Lee, Connie M. ; Li, XiaXin ; Loh, Mignon L. ; Clapp, D. ; Shannon, Kevin M. / Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. In: Blood. 2005 ; Vol. 106, No. 1. pp. 311-317.
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