Regulation of hematopoietic stem cells and leukemia stem cells by thrombopoietin

 描述(申请人提供)：造血干细胞(HSCs)在一生中维持血液和免疫系统的动态平衡。它们受到骨髓中微环境的严格调控。越来越多的证据表明，慢性粒细胞白血病(CML)是由突变的造血干细胞引起的。这些患病的白血病干细胞(LSCs)劫持了HSC机制，以维持肿瘤的生长并导致复发。因此，根除LSCs是治愈CML的关键。导致CML中BCR/ABL活性突变的发现和针对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慢性粒细胞白血病的一线药物。虽然酪氨酸激酶抑制剂(如伊马替尼)可以控制疾病，但它们不能消除CML-SCs。一个主要的CML-SC抵抗机制是由骨髓细胞提供的保护。阐明生态位调节机制和针对生态位保护机制将有助于消除CML-SCs，以更好地治疗CML。然而，人们对LSC利基市场知之甚少。这项研究的目的是确定外源性因子促血小板生成素(TPO)是如何调节HSCs和LSCs的。TPO途径是维持小鼠和人类原始HSC所必需的。目前尚不清楚表达TPO的骨髓细胞在哪里为原始的HSCs创造了一个特殊的生态位。此外，尚不清楚TPO通路是否被CML-SCs“劫持”以维持其功能。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是体内维持HSC的重要功能来源。最后，我们将从功能上测试TPO在CML进展中的作用，重点是体内的CML-SCs。这些研究的结果不仅有望为骨髓利基如何调节HSC的自我更新和功能提供新的见解，而且还有可能在该利基中确定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.