NPM1突变急性髓性白血病CD34表达调控以及对预后影响的机制研究

NPM1突变急性髓性白血病（NPM1+AML）是新认识的、最常见的AML类型，表型为CD34-，而其它类型AML主要为CD34+。NPM1+AML中CD34表达下调的机制不明，其骨髓中仍存少量的CD34+白血病细胞。本课题组首次发现CD34+（>7%）是NPM1+AML独立的预后不良因素。本课题组提出假说：（1）NPM1突变是CD34表达下调主要分子机制。（2）CD34+NPM1+AML预后差的主要机制是由于CD34+白血病群含有LSC。拟进行（1）利用细胞系和原代细胞, 调控NPM1突变的表达来观察对CD34表达的影响（2）从原代白血病细胞分选并比较CD34+/CD38-、CD34+/CD38+、CD34-/CD38+、CD34-/CD38-群的表型、移植到NOD/SCID小鼠、观察凋亡、耐药蛋白、粘附分子表达。探讨NPM1+AML的CD34表达调控以及对预后影响的机制。

NPM1-mutated acute myeloid leukemia(NPM1+AML) is recently recognized and the most common subtype of AML (about 1/3). Most patients with NPM1+AML are CD34-negative(CD34-)and most other AML patients (except for APL) are CD34-postive(CD34+). The reason why CD34 expression is down-regulated in NPM1+AML remains elusive. Though the CD34 is down-regulated, there still exist small amount of CD34+ blasts in bone marrow of NPM1+AML patients. We recently found,fot the first time,that CD34 expression (>7% blasts) is an independent prognostic factor. CD34+NPM1+AML patients had a lower complete remission rate, higher relapse rate and lower long-term survival. Moreover most CD34+ blasts express leukemia stem cell (LSC)-like immunophenotype CD34+/CD38- in NPM1+AML.We hypothesized that down-regulation of CD34 in blasts of NPM1+AML is modified by the NPM1-mutation, and that CD34+ blasts with leukemic stem cell -like immunophenotype may result in the poor outcomes of CD34+ patients . To explore our hypothesis, we first investigate the association of NPM1-mutation with CD34 expression in cell line and primary leukemia cells. We then sort CD34+/CD38-、CD34+/CD38+、CD34-/CD38+、CD34-/CD38- blasts population in bone marrow of patients to investigate each population's biology and function, such as engraftment in NOD/SCID micee, gene expression profile, proliferation and apoptosis, drug-resistance associated protein and adhesion molecular. Clarifying the mechanism of CD34 down-regulation and the poor prognostic value of CD34 expression may contribute to design individual therapy to NPM1+AML.