Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
Therapy-Resistant Acute Myeloid Leukemia Stem Cells Are Resensitized to Venetoclax + Azacitidine by Targeting Fatty Acid Desaturases 1 and 2.
复制标题
DOI：
10.3390/metabo13040467
复制
发表时间：
2023-03-24
期刊：
影响因子：
4.1
通讯作者：
D'Alessandro A
中科院分区：
文献类型：
--
作者：
Culp-Hill R;Stevens BM;Jones CL;Pei S;Dzieciatkowska M;Minhajuddin M;Jordan CT;D'Alessandro A
最近，利用venetoclax联合阿扎胞苷（ven + aza）靶向白血病干细胞（LSCs）的研究进展显著改善了新生急性髓性白血病（AML）患者的预后。然而，传统化疗后复发的患者往往对venetoclax耐药，表现出较差的临床结果。我们之前描述了脂肪酸代谢驱动氧化磷酸化（OXPHOS），并作为复发/难治性AML中LSC存活的机制。在这里，我们报道了化疗复发的原发性AML表现出异常的脂肪酸和脂质代谢，以及通过脂肪酸去饱和酶1和2的活性增加的脂肪酸去饱和，脂肪酸去饱和酶作为循环NAD+的机制来驱动复发的LSC生存。当与even + aza联合使用时，脂肪酸去饱和的遗传和药理学抑制导致复发性AML的原发性AML生存能力降低。这项研究包括迄今为止最大的lsc富集的原发性AML患者细胞脂质组学分析，表明抑制脂肪酸去饱和是复发性AML的一个有希望的治疗靶点。
Recent advances in targeting leukemic stem cells (LSCs) using venetoclax with azacitidine (ven + aza) has significantly improved outcomes for de novo acute myeloid leukemia (AML) patients. However, patients who relapse after traditional chemotherapy are often venetoclax-resistant and exhibit poor clinical outcomes. We previously described that fatty acid metabolism drives oxidative phosphorylation (OXPHOS) and acts as a mechanism of LSC survival in relapsed/refractory AML. Here, we report that chemotherapy-relapsed primary AML displays aberrant fatty acid and lipid metabolism, as well as increased fatty acid desaturation through the activity of fatty acid desaturases 1 and 2, and that fatty acid desaturases function as a mechanism of recycling NAD+ to drive relapsed LSC survival. When combined with ven + aza, the genetic and pharmacologic inhibition of fatty acid desaturation results in decreased primary AML viability in relapsed AML. This study includes the largest lipidomic profile of LSC-enriched primary AML patient cells to date and indicates that inhibition of fatty acid desaturation is a promising therapeutic target for relapsed AML.
登录
查看更多内容
影响因子：
50.3
作者：
Jones CL;Stevens BM;D'Alessandro A;Reisz JA;Culp-Hill R;Nemkov T;Pei S;Khan N;Adane B;Ye H;Krug A;Reinhold D;Smith C;DeGregori J;Pollyea DA;Jordan CT
通讯作者：
Jordan CT
影响因子：
20.3
作者：
Tcheng, Matthew;Roma, Alessia;Spagnuolo, Paul A.
通讯作者：
Spagnuolo, Paul A.
影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
抑制线粒体翻译是人类急性髓样白血病的治疗策略。
影响因子：
50.3
作者：
Skrtić M;Sriskanthadevan S;Jhas B;Gebbia M;Wang X;Wang Z;Hurren R;Jitkova Y;Gronda M;Maclean N;Lai CK;Eberhard Y;Bartoszko J;Spagnuolo P;Rutledge AC;Datti A;Ketela T;Moffat J;Robinson BH;Cameron JH;Wrana J;Eaves CJ;Minden MD;Wang JC;Dick JE;Humphries K;Nislow C;Giaever G;Schimmer AD
通讯作者：
Schimmer AD
影响因子：
22.7
作者：
Stevens BM;Jones CL;Pollyea DA;Culp-Hill R;D'Alessandro A;Winters A;Krug A;Abbott D;Goosman M;Pei S;Ye H;Gillen AE;Becker MW;Savona MR;Smith C;Jordan CT
通讯作者：
Jordan CT