Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells

Dan Xu, Xia Liu, Wen Mei Yu, Howard J. Meyerson, Caiying Guo, Stanton L. Gerson, Cheng Kui Qu

Research output: Contribution to journalArticlepeer-review

93 Scopus citations

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. Ptpn11E76K 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 Ptpn11E76K conditional knock-in mice. Global Ptpn11E76K/+ 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 Ptpn11E76K/+ 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 Ptpn11E76K/+ mutation promotes LSC development, partly by causing centrosome amplification and genomic instability. Thus, Ptpn11E76K mutation has non-lineage-specific effects on malignant transformation of hematopoietic cells and initiates acute leukemias at various stages of hematopoiesis.

Original languageEnglish
Pages (from-to)1977-1988
Number of pages12
JournalJournal of Experimental Medicine
Volume208
Issue number10
DOIs
StatePublished - Sep 26 2011

Funding

FundersFunder number
National Heart, Lung, and Blood Institute (NHLBI)T32HL007910
National Heart, Lung, and Blood Institute (NHLBI)

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

    Fingerprint

    Dive into the research topics of 'Non-lineage/stage-restricted effects of a gain-of-function mutation in tyrosine phosphatase Ptpn11 (Shp2) on malignant transformation of hematopoietic cells'. Together they form a unique fingerprint.

    Cite this