Role of p21 activated kinase in Leukemogenesis

摘要 在前一个资金周期中，我们的研究主要集中在与转化机制(S)相关的研究上 用FLT3ITD和致癌试剂盒检测髓系白血病，包括AML和MPN。我们发现了新的信号 这些癌基因下游单独发挥作用以及与突变协同发挥作用的途径 在表观遗传调控基因TET2和DNMT3A中。这项竞争性续签申请的重点包括 更好地了解PI3Kinase/c-Myc/GCN2通路和p38αMAPK通路在乳腺癌中的作用 TET2介导的白血病前期细胞克隆性造血及其与Flt3ITD的协同作用 弗兰克·阿梅尔。我们最近提供的实验证据支持这样一种观点，即接触HSCP 体细胞TET2(10-11易位2，CH患者最常见的突变基因之一) 突变导致急性/慢性感染或高血糖(HG)，如糖尿病和肥胖症患者所注意到的， 深刻地加速了慢性肝炎和白血病的发展。我们表明，这在一定程度上是由于增强了 突变的HSCP产生炎性细胞因子，在前馈循环中驱动存活， 突变的HSCP扩增和自我更新，但诱导正常HSCP的凋亡和分化。 然而，HSCP中这些突变下游的信号机制(S)有助于其 增强蜂窝竞争力，这些都是未知的，也是这项提案的主要重点。确定这些 这些途径将使我们能够从治疗上针对这些突变细胞，从而降低它们的竞争力。 预防或减轻慢性肝炎、白血病和心血管疾病的发生。我们执行了一项无偏见的RNAseq分析 对WT和TET2 KO HSCP的研究及在TET2 KO HSCP中发现的几种信号转导途径 与WT相比。在此，我们重点研究了PI3Kinase/c-Myc/GCN2和p38 MAPK通路。 我们表明，这些途径提供了TET2突变的HSCP的竞争优势，但不是WT HSCP。 在TET2 KO HSCP中抑制这些通路，逆转和拯救，大量的细胞 与这些电池相关的竞争优势。我们将更详细地定义这些途径的作用。 此外，我们将确定这些通路改变下游功能的机制(S) 信号。

ABSTRACT During the previous funding cycle, our research focused on studies related to mechanism(s) of transformation by FLT3ITD and oncogenic KIT in myeloid leukemia’s including in AMLs and MPNs. We identified novel signaling pathways downstream from these oncogenes that function individually as well as in cooperation with mutations in epigenetic regulators such as TET2 and DNMT3A. The focus of this competitive renewal application involves a better understanding of the role of the PI3Kinase/c-Myc/GCN2 pathway as well as the p38α MAPK pathway in driving TET2 mediated clonal hematopoiesis (CH) in pre-leukemic cells and its cooperation with FLT3ITD driven frank AML. We recently provided experimental evidence supporting the notion that exposure of HSCPs with somatic TET2 (ten-eleven translocation 2, one of the most frequently mutated genes in individuals exhibiting CH) mutations to acute/chronic infection or hyperglycemia (HG), as noted in patients with diabetes and obesity, profoundly accelerates the development of CH and leukemia. We showed that this is in part due to enhanced production of inflammatory cytokines by mutant HSCPs, which in a feed-forward loop drive the survival, expansion and self-renewal of mutant HSCPs but induce apoptosis and differentiation in normal HSCPs. However, the signaling mechanism(s) downstream from these mutations in HSCPs, which contribute to their enhanced cellular competitiveness, are not known and the main focus of this proposal. Identifying these pathways would allow us to therapeutically target these mutant cells to mitigate their competitiveness thereby preventing or mitigating CH, development of leukemia and CVD. We performed an unbiased RNAseq analysis on WT and Tet2 KO HSCPs and identified several dysregulated signaling pathways in Tet2 KO HSCPs compared to WT. Here, we have focused our efforts on the PI3Kinase/c-Myc/GCN2 and the p38 MAPK pathway. We show that these pathways provide competitive advantage to Tet2 mutant HSCPs but not WT HSCPs. Inhibition of these pathways in Tet2 KO HSCPs, reverses and rescues, a significant number of cellular competitive advantages associated with these cells. We will define the role of these pathways in more detail. Furthermore, we will identify the mechanism(s) by which these pathways alter the function of downstream signals.