Regulation of hematopoietic stem cells and leukemia stem cells by thrombopoietin

 描述（由申请人提供）：造血干细胞（HSC）在整个生命过程中维持血液和免疫系统的稳态。它们受到骨髓中微环境生态位的严格调控。越来越多的证据表明，慢性粒细胞白血病（CML）是由突变的HSC引起的。这些患病的白血病干细胞（LSC）劫持HSC机制以维持癌症生长并导致复发。因此，根除LSC是治愈CML的关键。CML中引起活性Bcr/abl激酶突变的发现和针对Bcr/abl的酪氨酸激酶抑制剂的开发彻底改变了我们治疗CML的方式。酪氨酸抑制剂成为治疗CML的第一线药物。虽然酪氨酸激酶抑制剂（例如伊马替尼）可以控制疾病，但它们不能消除CML-SC。一个主要的CML-SC耐药机制是骨髓生态位提供的保护。阐明CML的生态位调控机制，针对其生态位保护机制，将有助于清除CML-SC，更好地治疗CML。然而，对LSC利基知之甚少。本研究的目的是探讨血小板生成素（TPO）作为一种外源性因子对HSC和LSC的调控作用。TPO途径是维持小鼠和人类原始HSC所必需的。表达TPO的骨髓细胞在哪里为原始HSC创造了一个特殊的生态位尚不清楚。此外，尚不清楚TPO途径是否被CML-SC“劫持”以维持其维持。在这里，我们将确定TPO在骨髓中的细胞来源。然后，我们将测试哪些细胞代表HSC在体内维持的重要功能来源。最后，我们将在功能上测试TPO在CML进展中的作用，重点是体内CML-SC。这些研究的结果不仅有望为骨髓小生境如何调节HSC自我更新和功能提供新的见解，而且有可能在小生境中确定CML的治疗靶点。

 DESCRIPTION (provided by applicant): Hematopoietic stem cells (HSCs) maintain homeostasis of the blood and immune system throughout life. They are tightly regulated by their microenvironmental niche in the bone marrow. Mounting evidence suggests that chronic myeloid leukemia (CML) arise from mutant HSCs. These diseased leukemia stem cells (LSCs) hijack the HSC mechanisms to sustain the cancer growth and cause relapse. Eradication of LSCs is thus pivotal to cure CML. The discovery of the causing active Bcr/abl kinase mutation in CML and the development of tyrosine kinase inhibitors against Bcr/abl have revolutionized the way we treat CML. Tyrosine inhibitors become the first line of treatment against CML. Although tyrosine kinase inhibitors (e.g. imatinib) can manage the disease, they do not eliminate CML-SCs. A major CML-SC resistant mechanism is the protection offered by the bone marrow niche. Elucidating the niche regulatory mechanisms and target the niche protection mechanisms will help eliminate CML-SCs to better treat CML. However, little is known about the LSC niche. The goal of the proposed research is to characterize how thrombopoietin (TPO), an extrinsic factor, regulates HSCs and LSCs. TPO pathway is required for primitive HSC maintenance in mice and humans. It is not known where Tpo-expressing bone marrow cells create a special niche for primitive HSCs. Furthermore it is not known whether TPO pathway is `hijacked' by CML-SCs for their maintenance. Here, we will identify cellular source of TPO in the bone marrow. Then we will test what cells represent functionally important source for HSC maintenance in vivo. Finally, we will functionally test the role of TPO in CML progression with the focus on CML-SCs in vivo. The results of these studies are expected to not only provide new insights on how the bone marrow niche regulates HSC self-renewal and function, but also have the potential to identify therapeutic targets for CML in the niche.