Targeted Therapy of Lyn in Myelodysplastic Syndrome

描述（由申请人提供）：骨髓增生异常综合征（MDS）是一种发病率越来越高的疾病，对其病理生理学的了解很少，除非进行同种异体干细胞移植，否则无法治愈。由于大多数患者是老年人，迫切需要新的治疗策略。MDS从克隆造血失调发展为急性髓性白血病（AML）。在早期MDS中，高细胞骨髓中存在加速的血细胞凋亡。在MDS晚期，细胞凋亡缺失，分化受阻。我们的实验室一直在研究粒细胞集落刺激因子（G-CSF）刺激细胞的信号通路。异常的G-CSF受体信号在几种形式的儿童和成人MDS中发现：1)患有严重先天性中性粒细胞减少症的儿童发展为MDS/AML的风险增加10,000倍-几乎所有人都表达截断的G-CSF受体；2)分化缺陷的G-CSF受体亚型在AML、MDS和单体7患者中表达升高；3)在MDS患者中存在影响G-CSF受体远端结构域的功能多态性。因此，我们假设由于G-CSF受体信号传导功能障碍导致的骨髓生成紊乱是一些MDS病例的基础，而靶向治疗可能成功延缓或预防白血病转化。我们已经确定Src激酶Lyn是G-CSF受体信号传导的主要效应因子。主要局限于血细胞，Lyn提供了一个可行的药物靶点。为了解决这些假设，我们提出以下具体目标：1)表征由G-CSF受体远端结构域驱动的lynn依赖性生长控制通路并确定其在原代MDS细胞中的存在；2)描述IV类G-CSF受体表达增加及其在MDS原代细胞中的存在所引起的信号变化；3)在小鼠模型和细胞系上测试Lyn靶向治疗的效果。这些研究将为使用Src抑制剂治疗MDS患者亚群的II期研究提供依据。

DESCRIPTION (provided by applicant): Myelodysplastic Syndromes (MDS) are a disorder, increasing in frequency, for which there is poor understanding of its pathophysiology and no curative therapy short of an allogeneic stem cell transplant. Since most patients are elderly, new therapeutic strategies are desperately needed. MDS evolves from dysregulated clonal hematopoiesis to acute myeloid leukemia (AML). In early MDS, there is accelerated apoptosis of blood cells in a hypercellular bone marrow. In late MDS, apoptosis is deficient and a block in differentiation occurs. Our laboratory has been studying signaling pathways in cells stimulated by Granulocyte Colony-Stimulating Factor (G-CSF). Abnormal G-CSF Receptor signaling is found in several forms of pediatric and adult MDS: 1) children with severe congenital neutropenia have a 10,000-fold increase risk of developing MDS/AML - almost all of whom express a truncated G-CSF Receptor; 2) expression of the differentiation-defective G-CSF Receptor isoform is elevated in AML, MDS, and monosomy 7 patients; 3) a functional polymorphism affecting the distal, domain of the G-CSF Receptor occurs in MDS patients. Therefore, we hypothesize that disordered myelopoiesis due to dysfunctional G-CSF Receptor signaling underlies some cases of MDS and that targeted therapy may successfully delay or prevent leukemic transformation. We have identified the Src kinase Lyn as a major effector of G-CSF Receptor signaling. Chiefly limited to blood cells, Lyn provides a feasible drug target. To address these hypotheses, we propose the following specific aims: 1) Characterize the Lyn-dependent growth controlling pathways driven by the distal domain of the G-CSF Receptor and determine their presence in primary MDS cells; 2) Characterize the signaling changes due to increased expression of Class IV G-CSF Receptor and its presence in primary MDS cells; and 3) Test the effect of Lyn targeted therapy in mouse model and cell lines. These studies will provide rationale for a phase II study using Src inhibitors for subsets of MDS patients.