Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA.
Curr Opin Hematol. 2012 Jul;19(4):273-9. doi: 10.1097/MOH.0b013e328353c6bf.
The protein tyrosine phosphatase Shp2 is encoded by PTPN11 and positively regulates physiologic hematopoiesis. Mutations of PTPN11 cause the congenital disorder Noonan syndrome and pathologically promote human leukemias. Given the high frequency of PTPN11 mutations in human disease, several animal models have been generated to investigate Shp2 in hematopoietic stem cell (HSC) function and leukemic transformation.
Two independent animal models bearing knockout of Shp2 in hematopoietic tissues clearly demonstrate the necessity of Shp2 in HSC repopulating capacity. Reduced HSC quiescence and increased apoptosis accounts for diminished HSC function in the absence of Shp2. The germline mutation Shp2D61G enhances HSC activity and induces myeloproliferative disease (MPD) in vivo by HSC transformation. The somatic mutation Shp2D61Y produces MPD in vivo but fails to induce acute leukemia, whereas somatic Shp2E76K produces MPD in vivo that transforms into full-blown leukemia. HSCs expressing Shp2D61Y do not generate MPD in recipient animals upon transplantation, whereas Shp2E76K-expressing HSCs yield MPD as well as acute leukemia in recipient animals. The mechanisms underlying the unique functions of Shp2D61Y and Shp2E76K in HSC transformation and leukemogenesis continue to be under investigation.
Further understanding of the physiologic and pathologic role of Shp2 in hematopoiesis and leukemogenesis, respectively, will yield information needed to develop therapeutic strategies targeted to Shp2 in human disease.
蛋白酪氨酸磷酸酶 Shp2 由 PTPN11 编码，正向调控生理性造血。PTPN11 的突变可导致先天性疾病诺南综合征，并病理性促进人类白血病。鉴于 PTPN11 突变在人类疾病中的高频率，已经生成了几种动物模型来研究 Shp2 在造血干细胞（HSC）功能和白血病转化中的作用。
两种独立的造血组织 Shp2 敲除动物模型清楚地表明了 Shp2 在 HSC 再生能力中的必要性。Shp2 的缺失导致 HSC 静止减少和凋亡增加，从而导致 HSC 功能下降。生殖系突变 Shp2D61G 通过 HSC 转化增强 HSC 活性并在体内诱导骨髓增生性疾病（MPD）。体细胞突变 Shp2D61Y 在体内产生 MPD，但不能诱导急性白血病，而体细胞 Shp2E76K 在体内产生 MPD，并转化为完全性白血病。在移植后，表达 Shp2D61Y 的 HSCs 不会在受体动物中产生 MPD，而表达 Shp2E76K 的 HSCs 在受体动物中产生 MPD 以及急性白血病。Shp2D61Y 和 Shp2E76K 在 HSC 转化和白血病发生中的独特功能的机制仍在研究中。
进一步了解 Shp2 在造血和白血病发生中的生理和病理作用，将为开发针对人类疾病中 Shp2 的治疗策略提供所需信息。
