Leukemogenic Ptpn11 causes fatal myeloproliferative disorder via cell-autonomous effects on multiple stages of hematopoiesis.

PTPN11, which encodes the tyrosine phosphatase SHP2, is mutated in approximately 35% of patients with juvenile myelomonocytic leukemia (JMML) and at a lower incidence in other neoplasms. To model JMML pathogenesis, we generated knockin mice that conditionally express the leukemia-associated mutant Ptpn11(D61Y). Expression of Ptpn11(D61Y) in all hematopoietic cells evokes a fatal myeloproliferative disorder (MPD), featuring leukocytosis, anemia, hepatosplenomegaly, and factor-independent colony formation by bone marrow (BM) and spleen cells. The Lin(-)Sca1(+)cKit(+) (LSK) compartment is expanded and "right-shifted," accompanied by increased stem cell factor (SCF)-evoked colony formation and Erk and Akt activation. However, repopulating activity is decreased in diseased mice, and mice that do engraft with Ptpn11(D61Y) stem cells fail to develop MPD. Ptpn11(D61Y) common myeloid progenitors (CMPs) and granulocyte-monocyte progenitors (GMPs) produce cytokine-independent colonies in a cell-autonomous manner and demonstrate elevated Erk and Stat5 activation in response to granulocyte-macrophage colony-stimulating factor (GM-CSF) stimulation. Ptpn11(D61Y) megakaryocyte-erythrocyte progenitors (MEPs) yield increased numbers of erythrocyte burst-forming units (BFU-Es), but MEPs and erythrocyte-committed progenitors (EPs) produce fewer erythrocyte colony-forming units (CFU-Es), indicating defective erythroid differentiation. Our studies provide a mouse model for Ptpn11-evoked MPD and show that this disease results from cell-autonomous and distinct lineage-specific effects of mutant Ptpn11 on multiple stages of hematopoiesis.

[1]  B. Neel,et al.  Flow-Cytometric Phosphoprotein Analysis Reveals Agonist and Temporal Differences in Responses of Murine Hematopoietic Stem/Progenitor Cells , 2008, PloS one.

[2]  Jonathan M Irish,et al.  Single-cell profiling identifies aberrant STAT5 activation in myeloid malignancies with specific clinical and biologic correlates. , 2008, Cancer cell.

[3]  P. Emanuel.  Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia , 2008, Leukemia.

[4]  E. Passegué,et al.  The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells. , 2008, Cell stem cell.

[5]  Sandra A. Moore,et al.  Efficacy of TG101348, a selective JAK2 inhibitor, in treatment of a murine model of JAK2V617F-induced polycythemia vera. , 2008, Cancer cell.

[6]  G. Noronha,et al.  Selective inhibition of JAK2-driven erythroid differentiation of polycythemia vera progenitors. , 2008, Cancer cell.

[7]  Hao Wang,et al.  Constitutive activation of SHP2 in mice cooperates with ICSBP deficiency to accelerate progression to acute myeloid leukemia. , 2008, The Journal of clinical investigation.

[8]  B. Neel,et al.  The tyrosine phosphatase Shp2 (PTPN11) in cancer , 2008, Cancer and Metastasis Reviews.

[9]  D. Scadden,et al.  Limiting factors in murine hematopoietic stem cell assays. , 2007, Cell stem cell.

[10]  Suzanne Schubbert,et al.  Hyperactive Ras in developmental disorders and cancer , 2007, Nature Reviews Cancer.

[11]  R. Jaenisch,et al.  Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways. , 2007, Blood.

[12]  S. Orkin,et al.  Rb Regulates Interactions between Hematopoietic Stem Cells and Their Bone Marrow Microenvironment , 2007, Cell.

[13]  P. Chambon,et al.  A Microenvironment-Induced Myeloproliferative Syndrome Caused by Retinoic Acid Receptor γ Deficiency , 2007, Cell.

[14]  G. Nolan,et al.  K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. , 2007, Blood.

[15]  D. Largaespada,et al.  Beta common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice. , 2007, Blood.

[16]  B. Neel,et al.  The role of Shp2 (PTPN11) in cancer. , 2007, Current opinion in genetics & development.

[17]  G. Feng,et al.  PTPN11 is the first identified proto-oncogene that encodes a tyrosine phosphatase. , 2007, Blood.

[18]  T. Jacks,et al.  Somatic activation of a conditional KrasG12D allele causes ineffective erythropoiesis in vivo. , 2006, Blood.

[19]  Yan Liu,et al.  The transcription factor MEF/ELF4 regulates the quiescence of primitive hematopoietic cells. , 2006, Cancer cell.

[20]  Malcolm McGregor,et al.  Diverse Biochemical Properties of Shp2 Mutants , 2005, Journal of Biological Chemistry.

[21]  Bruce D Gelb,et al.  Noonan syndrome and related disorders: genetics and pathogenesis. , 2005, Annual review of genomics and human genetics.

[22]  S. Morrison,et al.  Supplemental Experimental Procedures , 2022 .

[23]  Menggang Yu,et al.  Human somatic PTPN11 mutations induce hematopoietic-cell hypersensitivity to granulocyte-macrophage colony-stimulating factor. , 2005, Blood.

[24]  Claudia Waskow,et al.  Prospective isolation and global gene expression analysis of the erythrocyte colony-forming unit (CFU-E). , 2005, Blood.

[25]  J. Kutok,et al.  Prognostic, therapeutic, and mechanistic implications of a mouse model of leukemia evoked by Shp2 (PTPN11) mutations. , 2005, Cancer cell.

[26]  M. Loh,et al.  Functional analysis of leukemia-associated PTPN11 mutations in primary hematopoietic cells. , 2004, Blood.

[27]  U. Klingmüller,et al.  A mouse model for visualization and conditional mutations in the erythroid lineage. , 2004, Blood.

[28]  D. Gilliland,et al.  Mouse model of Noonan syndrome reveals cell type– and gene dosage–dependent effects of Ptpn11 mutation , 2004, Nature Medicine.

[29]  M. L. Le Beau,et al.  Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder. , 2004, Blood.

[30]  J. Kutok,et al.  Conditional expression of oncogenic K-ras from its endogenous promoter induces a myeloproliferative disease. , 2004, The Journal of clinical investigation.

[31]  T. Jacks,et al.  Somatic activation of oncogenic Kras in hematopoietic cells initiates a rapidly fatal myeloproliferative disorder. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[32]  Harvey F Lodish,et al.  Role of Ras signaling in erythroid differentiation of mouse fetal liver cells: functional analysis by a flow cytometry-based novel culture system. , 2003, Blood.

[33]  Andrew P McMahon,et al.  Efficient recombination in diverse tissues by a tamoxifen-inducible form of Cre: a tool for temporally regulated gene activation/inactivation in the mouse. , 2002, Developmental biology.

[34]  Michael A. Patton,et al.  Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome , 2001, Nature Genetics.

[35]  K. Shannon,et al.  Quantitative effects of Nf1 inactivation on in vivo hematopoiesis. , 2001, The Journal of clinical investigation.

[36]  T. Jacks,et al.  Nf1 and Gmcsf interact in myeloid leukemogenesis. , 2000, Molecular cell.

[37]  D. Barford,et al.  Revealing mechanisms for SH2 domain mediated regulation of the protein tyrosine phosphatase SHP-2. , 1998, Structure.

[38]  S. Shoelson,et al.  Crystal Structure of the Tyrosine Phosphatase SHP-2 , 1998, Cell.

[39]  F. Alt,et al.  Efficient in vivo manipulation of mouse genomic sequences at the zygote stage. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[40]  M Aguet,et al.  Inducible gene targeting in mice , 1995, Science.

[41]  P. Emanuel,et al.  Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. , 1991, Blood.

[42]  R. Baehner,et al.  Juvenile "chronic granulocytic" leukemia: a panmyelopathy with prominent monocytic involvement and circulating monocyte colony-forming cells. , 1974, Blood.