Germline mutations of PTPN11 (SHP-2) in the stem cell microenvironment

Project: Research projectResearch Project


Project SummaryPatients with Noonan syndrome (NS), a developmental disorder characterized by congenital heartdisease, dysmorphic facial structures, short stature, and mental retardation, are at an increased risk ofdeveloping leukemias, especially juvenile myelomonocytic leukemia (JMML), a fatal childhoodmyeloproliferative neoplasm (MPN). The mechanisms underlying the leukemogenesis are not completelyunderstood. Lack of such knowledge impedes the development of therapeutic interventions for effectivelycontrolling leukemic progression in NS and for improving treatment outcomes in NS-associatedleukemias. Germline activating mutations of PTPN11 (encoding SHP2), a protein tyrosine phosphatasethat we previously demonstrated is required for embryogenesis and hematopoietic cell development, areassociated with more than 50% of patients with NS. Studies from our laboratory and others haveestablished a cell-intrinsic role of PTPN11 mutations in NS and associated leukemias. Intriguingly, ourmost recent studies suggest that PTPN11 mutations in the bone marrow (BM) microenvironment canalso induce a profound myeloid malignancy. The objective of the current project is to determine thecellular and molecular mechanisms by which PTPN11 mutated microenvironmental cells impact residenthematopoietic stem cells. The central hypothesis of the proposal is that germline PTPN11 mutations inthe BM microenvironment greatly promote the leukemic progression in NS and cause stem celltransplantation failure. We plan to test this hypothesis and accomplish the objective of this application bypursuing the following aims. 1). Identify the cellular components and protein factors that mediate theleukemogenic effects of PTPN11 mutations in the BM microenvironment. 2). Determine the molecularmechanisms by which PTPN11 mutations change the activities of microenvironmental cells. 3). validatethe pathogenic effects of PTPN11 mutations in NS patient-derived BM microenvironmental cells. Thisproject will not only greatly advance our understanding of the pathogenesis of NS-associated leukemias,but also provide a molecular basis for the rational design of new therapeutics targeting the detrimentalmicroenvironment in NS patients, which may eventually lead to significant improvements in controllingleukemic progression in NS and in stem cell transplantation therapy for NS-associated leukemias.
Effective start/end date8/5/166/30/20


  • National Institutes of Health: $390,000.00


Noonan Syndrome
Stem Cell Niche
Germ-Line Mutation
Bone Marrow
Juvenile Myelomonocytic Leukemia
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
Stem Cell Transplantation
Cell- and Tissue-Based Therapy
Intellectual Disability
Bone Marrow Cells
Embryonic Development
Stem Cells