Regulation of normal and leukemic hematopoiesis by type I interferon

描述（由申请人提供）：该项目的目标是确定I型ifn改变未成熟造血干细胞（hsc）和祖细胞命运的机制，并确定I型ifn对正常和白血病造血干细胞的健康和潜能的影响和潜在机制。这些研究将使用从野生型小鼠和从人慢性髓性白血病（CML）的SCLtTAxBCR/ABL双转基因小鼠模型中分离的造血干细胞和祖细胞，以及一系列全面的体内和体外实验方法进行。在第一个目标中，我们将研究短期（天）和长期（周）暴露于I型ifn如何影响造血干细胞和祖细胞的生物学，包括它们的静止、增殖、潜能和对凋亡的易感性。我们还将研究慢性（数月）暴露于I型ifn是否会损害HSC的自我更新。最后，我们将定义这些变化背后的分子机制。在第二个目标中，我们将评估I型ifn与野生型细胞相比如何影响白血病造血干细胞和祖细胞的生物学。我们将研究表达BCR/ABL的白血病造血干细胞的解除调控特性（即增殖增加、静止减少、存活增加）如何改变它们对I型ifn暴露的反应，并可能使它们对I型ifn和BCR/ABL酪氨酸激酶抑制剂伊马替尼联合治疗敏感。综上所述，这些方法应该揭示炎症信号（如I型ifn）如何影响正常控制HSC和祖细胞稳态的调节网络，以及白血病HSC的不受调节特性如何改变它们对炎症信号和治疗干预影响的敏感性。

DESCRIPTION (provided by applicant): The goals of this project are to define the mechanisms by which type I IFNs alter the fates of immature hematopoietic stem cells (HSCs) and progenitor cells, and to identify the effect and underlying mechanisms of type I IFNs on the health and potential of normal and leukemic HSCs. These studies will be carried out using HSCs and progenitor cells isolated from wild-type mice and from the SCLtTAxBCR/ABL double transgenic mouse model of human chronic myelogenous leukemia (CML), and a comprehensive array of in vivo and in vitro experimental approaches. In the first aim, we will investigate how short-term (days) and long-term (weeks) exposure to type I IFNs affects the biology of HSCs and progenitor cells with respect to their quiescence, proliferation, potential, and susceptibility to apoptosis. We will also examine whether chronic (months) exposure to type I IFNs damages HSC self-renewal. Lastly, we will define the molecular mechanisms underlying these changes. In the second aim, we will assess how type I IFNs affect the biology of leukemic HSCs and progenitor cells compared to wild type cells. We will investigate how the deregulated properties of BCR/ABL-expressing leukemic HSCs (i.e., increased proliferation, decreased quiescence, increase survival) change their response to type I IFNs exposure and may sensitize them to combinatorial treatments with type I IFNs and the BCR/ABL tyrosine kinase inhibitor, Imatinib. Taken together, these approaches should uncover how inflammatory signals such as type I IFNs impact on the regulatory networks that normally control HSC and progenitor cell homeostasis, and how the deregulated properties of leukemic HSCs may alter their sensitivity to the effects of inflammatory signals and therapeutic interventions. PUBLIC HEALTH RELEVANCE: This project seeks to understand how type I interferons (IFNs), a large family of inflammatory proteins, affects the biology of hematopoietic stem cells (HSCs), a small population of bone marrow cells that generate all blood cells. Improper regulation of HSC activity can lead to a number of severe blood diseases. These include chronic myelogenous leukemia (CML), which has long been treated with type I IFNs despite the lack of knowledge regarding their mechanism of action. Recent clinical work suggests that type I IFNs may enhance the curative effect of other CML treatments, such as the tyrosine kinase inhibitor Imatinib. By uncovering how type I IFNs affect the biology of normal and leukemic HSCs, and the molecular mechanisms underlying these effects, the proposed work could be of significant value to public health by providing the basis for the design of more effective co-treatments for CML and other blood diseases that will harness the beneficial effect of type I IFNs.