Shp2 and Pten in Leukemia and Anemia

 描述（由申请人提供）：本项目的目标是破译造血和血液病中细胞类型特异性信号通路的串扰。我们的新的和令人惊讶的数据表明，两个众所周知的信号调节因子Pten和Shp 2可以在不同的血细胞谱系中协同或拮抗地工作，这一应用是被迫的。因此，在不同细胞类型中信号相互作用的结果不能简单地从先前已知的每个分子的功能推断出来。 Shp 2是一种非受体酪氨酸磷酸酶，具有两个SH 2结构域，促进Erk信号传导，PTPN 11/Shp 2中的显性激活突变具有致白血病作用。表达Shp 2抑制小鼠造血干细胞（HSC）和祖细胞增殖和分化，确定了Shp 2在造血中的积极作用。相比之下，Pten（磷酸酶和张力蛋白同源物）是负调节PI 3 K/Akt通路的肿瘤抑制因子，并且在人类白血病中经常突变。Pten的靶向缺失导致短期HSC（ST-HSC）的急剧扩增、骨髓细胞过度增殖和白血病的发展。 为了测试Pten和Shp 2是否在白血病发生中具有直接相反的功能，我们产生了条件性Pten和Shp 2双敲除（DKO）小鼠。初步数据表明，如预期的那样，额外的Shp 2缺失确实抑制了由Pten缺乏诱导的过度骨髓细胞增殖和白血病，但令人惊讶的是Pten和Shp 2 DKO小鼠发展出致命性贫血。这些结果表明，尽管Shp 2和Pten在髓系细胞中具有拮抗作用，但这两种调节剂共同促进红细胞（RBC）的发育和成熟。本申请试图阐明Shp 2和Pten在血细胞中的对立以及协同功能。我们将阐明Shp 2和Pten调制信号的细胞类型特异性串扰的分子机制。该项目的成功不仅将促进我们对哺乳动物中驱动造血的相互作用分子途径的理解，还将为白血病和贫血提供更好的治疗策略。

 DESCRIPTION (provided by applicant): The goal of this project is to decipher cell type-specific crosstalk of signaling pathways in hematopoiesis and hematological diseases. This application is compelled by our new and surprising data indicating that two well-known signal regulators, Pten and Shp2, can work cooperatively or antagonistically in different blood cell lineages. Thus, the outcome of signal interplay in different cell types cannot be simply deduced from previously known functions for each molecule. Shp2 is a non-receptor tyrosine phosphatase possessing two SH2 domains that promotes Erk signaling, and dominantly activating mutations in PTPN11/Shp2 have leukemogenic effect. Ablating Shp2 suppressed hematopoietic stem cell (HSC) and progenitor cell proliferation and differentiation in mice, defining a positive role of Shp2 in hematopoiesis. In contrast, Pten (phosphatase and tensin homolog) is a tumor suppressor that negatively regulates the PI3K/Akt pathway and is frequently mutated in human leukemia. Targeted deletion of Pten resulted in dramatic expansion of short-term HSCs (ST-HSCs), excessive myeloid cell proliferation and development of leukemia. To test whether Pten and Shp2 have directly opposing functions in leukemogenesis, we generated conditional Pten and Shp2 double knockout (DKO) mice. Preliminary data suggest that additional deletion of Shp2 indeed suppressed excessive myeloid cell proliferation and leukemia induced by Pten-deficiency as expected, but surprisingly the Pten and Shp2 DKO mice developed lethal anemia. These results argue that although Shp2 and Pten have antagonistic roles in myeloid cells, these two regulators act in concert to promote red blood cell (RBC) development and maturation. This application seeks to elucidate the opposing as well as cooperating functions of Shp2 and Pten in blood cells. We will elucidate the molecular mechanisms underlying the cell type-specific crosstalk of Shp2- and Pten-modulated signals. The success of this project will not only advance our understanding of the interactive molecular pathways driving hematopoiesis in mammals, but also suggest better therapeutic strategies for leukemia and anemia.