不同表观遗传学机制调控FANCF及PARP1介导的急性粒细胞白血病耐药性机理研究

急性粒细胞白血病（AML）耐药性是当前临床治疗的重点和难点，其中范可尼贫血(FA)及其合成致死DNA修复通路活性缺失或增强是其耐药性发生的一个关键。我们初步研究表明耐药性AML根据FANCF及合成致死基因PKL1，PARP1表达程度可分为三个亚型：FANCF-/PLK1-/PARP1L（低表达PARP1），FANCF-/PLK1+/PARP1H（高表达PARP1）和FANCF+/PLK1+/PARP1M（中表达PARP1）。 我们提出PARP1介导的DNMT1活性抑制，使PLK1启动子去甲基化修饰是产生FANCF-/PLK1+/PARP1H耐药性的关键；根据合成致死原则，使用PARPs抑制剂为此亚型治疗策略。而过甲基化修饰SHP1上调JAK/STAT通路导致FANCF升高是FANCF+/PLK1+/PARP1M耐药性的机理，提出单独使用甲基化酶抑制剂或联合PARPs抑制剂为此亚型治疗策略。

Chemorefraction of AML (acute myeloid leukemia) is the most important and difficult clinical barriers that need to be overcome for it therapy. The defective or over-active FA (fanconi anemia) or its synthetic lethality DNA repair pathways is one of the key mechasnims for AML chemorefraction. Based on the expression profiles of FANCF and its synthetic lethality couterparters PKL1(polo-like kinase 1), PARP1(poly (ADP-ribose) polymerase 1), we have shown that chemorefractory AML can be categorized into three subtypes: FANCF-/PLK1-/PARP1L(low level expression of PARP1), FANCF-/PLK1+/PARP1H (high expression of PARP1) and FANCF+/PLK1+/PARP1M（moderate expression of PARP1). We hypotheize that PARP1 mediated hypomethylation of PLK1 promoter through inhibition of DNMT1 plays an important role in chemorefraction of FANCF-/PLK1+/PARP1H subtype AML, proposing PARPs inhibitors for a therapuetical strategy based on synthetic lethality principle. While SHP1 hypermethylation mediated activation of JAK/STAT is the key component for upregulation of FANCF in FANCF+/PLK1+/PARP1M subtype AML, in which we propose to use methylation inhibitors alone or combination with PARPs inihibitors for the therapeutical strategy for this subtype.