Overexpression of Shp2 tyrosine phosphatase is implicated in leukemogenesis in adult human leukemia

Department of Hematology, Second Affiliated Hospital, School of Medicine, Cancer Institute, Zhejiang University, Zhejiang Academy of Medical Sciences, Hangzhou, Zhejiang 310009, China.
Blood (Impact Factor: 10.45). 12/2005; 106(9):3142-9. DOI: 10.1182/blood-2004-10-4057
Source: PubMed


Shp2 tyrosine phosphatase plays a critical role in hematopoiesis, and dominant active mutations have been detected in the human gene PTPN11, encoding Shp2, in child leukemia patients. We report here that although no such mutations were detected in 44 adult leukemia patients screened, Shp2 expression levels were significantly elevated in primary leukemia cells and leukemia cell lines, as compared with normal hematopoietic progenitor cells. The Shp2 protein amounts correlated well with the hyperproliferative capacity but were inversely associated with the differentiation degree of leukemia cells. Suppression of Shp2 expression induced apoptosis and inhibition of leukemic cell clonogenic growth. Notably, the majority of Shp2 was preferentially localized to the plasma membrane and was constitutively phosphorylated on tyrosine in leukemia cells, and also in normal hematopoietic cells following mitogenic stimulation. Based on these results, we propose that aberrantly increased expression of Shp2 may contribute, collaboratively with other factors, to leukemogenesis.

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    • "PTPN11 encodes src homology 2 domain-containing protein-tyrosine phosphatase 2 (SHP2), a tyrosine phosphatase with critical cell properties, including the regulation of proliferation, apoptosis, and differentiation (7). SHP2 expression levels are elevated in AML and are related to the hyperproliferative capacity and the degree of differentiation of primary leukemia cells (8). Animal models lacking SHP2 expression in hematopoietic tissues presented peripheral blood and bone marrow cytopenia (9,10), in addition to increased apoptosis and a reduced quiescence and repopulation capacity of hematopoietic stem cells (10). "
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    • "In another study, by Xu et al., Shp2 [Src homology 2 (SH2) domain-containing phosphotyrosine phosphatase 2] expression was investigated in 20 patients with AML, 12 patients with acute lymphocytic leukemia (ALL), 18 with chronic myeloid leukemia (CML), one with chronic lymphocytic leukemia (CLL), and one patient diagnosed with biphenotypic leukemia [14]. Comparison of primary leukemia cells with normal hematopoietic progenitor cells demonstrates that Shp2 expression significantly increased in primary leukemia cells. "
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    • "In this work, we studied the role of Shp2 in FcεRΙ signaling utilizing Shp2-specific shRNAs expressed by retroviruses to inhibit Shp2 expression in RBL cells. Although previous reports have demonstrated a crucial contribution of Shp2 in development [35], proliferation [29], [36]–[38], and tumor suppression [39]–[41], little is known about the role of Shp2 in mast cell-dependent allergic reactions. Our results demonstrate an essential role of Shp2 in FcεRI-mediated RBL cell activation. "
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