Our previous studies have indicated a stringent requirement of SHP-2 tyrosine phosphatase for normal hematopoiesis, but little is known whether SHP-2 plays a role in human leukemogenesis. Here, we show that SHP-2 plays a pivotal role in regulating the proliferating potential of human leukemia cells. We identified three types of SHP-2 proteins: m-, n- and c-SHP-2 proteins from both leukemic and normal hematopoietic cells. The m- and n-SHP-2 proteins (termed as active SHP-2) are derived from the c-SHP-2 protein (inactive SHP-2), and highly expressed on the internal membrane of rapidly proliferating cells at S/G2 phase, and in nucleus of mitotic cells at prophase and prometaphase, respectively, whereas the c-SHP-2 protein is ubiquitously expressed in the cytoplasm of both proliferating and resting cells. Intriguingly, we found that both active SHP-2 protein and its mRNA were constitutively overexpressed in leukemic blasts from various human leukemia cell lines and nearly all cases of various subtypes of human leukemia tested, relative to normal hematopoietic progenitors. Moreover, the expression level of active SHP-2 protein is positively correlated with the hyperproliferative phenotype of leukemia patients, and inversely associated with differentiation degree of hematopoietic cells. Most importantly, block of SHP-2 expression induces apoptosis and growth inhibition of leukemic clonogenic cells both in vitro and in vivo. In addition, we found that both PI3k/Akt and Ras/Erk signaling pathways are constitutively activated in human leukemias. Finally, we identified no mutation in PTPN11 among all tested leukemia patients. Based on these findings, we propose that SHP-2 tyrosine phosphatase plays an essential role in human leukemogenesis in which it may directly controls the proliferative potential of neoplastic cells of human leukemia via regulating signaling pathways involved in survival, growth and apoptosis of leukemia cells such as PI3k/Akt and Ras/Erk signaling pathways.