title: Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells.
abstract: Activating mutations in protein tyrosine phosphatase 11 (Ptpn11) have been identified in childhood acute leukemias, in addition to juvenile myelomonocytic leukemia (JMML), which is a myeloproliferative disorder (MPD). It is not clear whether activating mutations of this phosphatase play a causal role in the pathogenesis of acute leukemias. If so, the cell origin of leukemia-initiating stem cells (LSCs) remains to be determined. Ptpn11(E76K) mutation is the most common and most active Ptpn11 mutation found in JMML and acute leukemias. However, the pathogenic effects of this mutation have not been well characterized. We have created Ptpn11(E76K) conditional knock-in mice. Global Ptpn11(E76K/+) mutation results in early embryonic lethality. Induced knock-in of this mutation in pan hematopoietic cells leads to MPD as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors. These animals subsequently progress to acute leukemias. Intriguingly, in addition to acute myeloid leukemia (AML), T cell acute lymphoblastic leukemia/lymphoma (T-ALL) and B-ALL are evolved. Moreover, tissue-specific knock-in of Ptpn11(E76K/+) mutation in lineage-committed myeloid, T lymphoid, and B lymphoid progenitors also results in AML, T-ALL, and B-ALL, respectively. Further analyses have revealed that Shp2 (encoded by Ptpn11) is distributed to centrosomes and that Ptpn11(E76K/+) mutation promotes LSC development, partly by causing centrosome amplification and genomic instability. Thus, Ptpn11(E76K) mutation has non-lineage-specific effects on malignant transformation of hematopoietic cells and initiates acute leukemias at various stages of hematopoiesis.
authors.affiliation: Department of Medicine, Division of Hematology and Oncology, Center for Stem Cell and Regenerative Medicine, Case Comprehensive Cancer Center, and Department of Pathology, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.forename: Xia
authors.initials: X
authors.lastname: Liu
authors.forename: Wen-Mei
authors.initials: WM
authors.lastname: Yu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Meyerson
authors.forename: Caiying
authors.initials: C
authors.lastname: Guo
authors.forename: Stanton L
authors.initials: SL
authors.lastname: Gerson
authors.forename: Cheng-Kui
authors.initials: CK
authors.lastname: Qu
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D019070:Cell Lineage; D002471:Cell Transformation, Neoplastic; D018385:Centrosome / Q000378:metabolism; D043171:Chromosomal Instability; D004622:Embryo, Mammalian / Q000473:pathology / Q000502:physiology; D055879:Gene Knock-In Techniques; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology*; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000473:pathology; D054429:Leukemia, Myelomonocytic, Juvenile / Q000235:genetics / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000235:genetics* / Q000378:metabolism
chemical_list: D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11