LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.
LKB1/STK11 Is a Tumor Suppressor in the Progression of Myeloproliferative Neoplasms.
复制标题
DOI：
10.1158/2159-8290.cd-20-1353
复制
发表时间：
2021-06
期刊：
影响因子：
28.2
通讯作者：
Crispino JD
中科院分区：
文献类型：
--
作者：
Marinaccio C;Suraneni P;Celik H;Volk A;Wen QJ;Ling T;Bulic M;Lasho T;Koche RP;Famulare CA;Farnoud N;Stein B;Schieber M;Gurbuxani S;Root DE;Younger ST;Hoffman R;Gangat N;Ntziachristos P;Chandel NS;Levine RL;Rampal RK;Challen GA;Tefferi A;Crispino JD
骨髓增生性肿瘤经常进展到急变期疾病，一种急性髓细胞白血病的侵袭性形式。为了鉴定抑制疾病进展的基因，我们进行了集中的CRISPR/Cas9筛选，发现LKB 1/Stk 11的缺失导致小鼠MPN细胞的体外自我更新增强。在小鼠MPN模型中Stk 11的缺失导致快速致死，骨髓中的纤维化、骨质疏松和未成熟细胞的积累增加，以及原代人MPN细胞在体内的植入增加。LKB 1丢失与线粒体ROS增加和HIF 1a稳定相关，在人原始细胞期MPN标本中观察到LKB 1下调和HIF 1a水平增加。值得注意的是，我们观察到在具有LKB 1损失的鼠MPN细胞中富集的途径与在母细胞期MPN患者标本中富集的途径的强烈一致性，支持STK 11是MPN中的肿瘤抑制因子的结论。
The myeloproliferative neoplasms frequently progress to blast phase disease, an aggressive form of acute myeloid leukemia. To identify genes that suppress disease progression, we performed a focused CRISPR/Cas9 screen and discovered that depletion of LKB1/Stk11 led to enhanced in vitro self-renewal of murine MPN cells. Deletion of Stk11 in a mouse MPN model caused rapid lethality with enhanced fibrosis, osteosclerosis and an accumulation immature cells in the bone marrow, as well as enhanced engraftment of primary human MPN cells in vivo. LKB1 loss was associated with increased mitochondrial ROS and stabilization of HIF1a, and downregulation of LKB1 and increased levels of HIF1a were observed in human blast phase MPN specimens. Of note, we observed strong concordance of pathways that were enriched in murine MPN cells with LKB1 loss with those enriched in blast phase MPN patient specimens, supporting the conclusion that STK11 is a tumor suppressor in the MPNs.