期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 112, 期 43, 页码 13342-13347出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1507599112
关键词
Pten; Shp2; myeloproliferative neoplasm; erythropoiesis; anemia
资金
- National Institutes of Health [R01HL129763, CA176012, CA188506, R01CA69202]
- National Natural Science Foundation of China [81270627]
- Science and Technology Commission of Shanghai Municipality Pujiang program [12PJ1406100]
- Shanghai Education Committee [12CG16, 13YZ030]
- Shanghai Institutions of Higher Learning
Previous data suggested a negative role of phosphatase and tensin homolog (Pten) and a positive function of SH2-containing tyrosine phosphatase (Shp2)/Ptpn11 in myelopoiesis and leukemogenesis. Herein we demonstrate that ablating Shp2 indeed suppressed the myeloproliferative effect of Pten loss, indicating directly opposing functions between pathways regulated by these two enzymes. Surprisingly, the Shp2 and Pten double-knockout mice suffered lethal anemia, a phenotype that reveals previously unappreciated cooperative roles of Pten and Shp2 in erythropoiesis. The lethal anemia was caused collectively by skewed progenitor differentiation and shortened erythrocyte lifespan. Consistently, treatment of Pten-deficient mice with a specific Shp2 inhibitor suppressedmyeloproliferative neoplasm while causing anemia. These results identify concerted actions of Pten and Shp2 in promoting erythropoiesis, while acting antagonistically in myeloproliferative neoplasm development. This study illustrates cell type-specific signal cross-talk in blood cell lineages, and will guide better design of pharmaceuticals for leukemia and other types of cancer in the era of precision medicine.
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