Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia.
Escape From Treatment; the Different Faces of Leukemic Stem Cells and Therapy Resistance in Acute Myeloid Leukemia.
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逃避治疗；急性髓系白血病白血病干细胞的不同面貌及其治疗耐药性。
DOI：
10.3389/fonc.2021.659253
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发表时间：
2021
影响因子：
4.7
通讯作者：
Smit L
中科院分区：
文献类型：
--
作者：
van Gils N;Denkers F;Smit L
多年来，标准诱导化疗一直是治疗急性髓系白血病(AML)的一线治疗方法。虽然这种治疗在大多数患者中导致完全缓解，但许多患者面临复发(适应性耐药)或难治性疾病(原发耐药)。此外，老年患者通常不适合以细胞毒为基础的治疗。AML复发是由于耐药白血病细胞存活(微小残留病，MRD)。具有干细胞特征的白血病细胞，称为白血病干细胞(LSCs)，存在于MRD中，被认为是复发起始的起源。人们越来越认识到白血病“顽固者”是由白血病内的异质性和导致治疗反应可塑性的非遗传因素引起的。BCL2抑制剂万托克拉克斯与去甲基化药物或小剂量阿糖胞苷联合使用，是一种重要的新疗法，尤其是对老年AML患者。然而，通常也有一小部分AML细胞对万乃馨治疗无效。由于AML MRD反映了治疗耐药机制的总和，治疗“持久者”和LSCs的不同方面可能被利用来达到最佳的治疗反应，防止复发的开始。在这里，我们描述了治疗敏感和耐药AML(干细胞)群体和LSCs的不同表观遗传、转录和代谢状态，这些细胞状态如何受到微环境的影响并影响AML的治疗结果。此外，我们还讨论了针对动态治疗耐药和LSCs的潜在策略。
Standard induction chemotherapy, consisting of an anthracycline and cytarabine, has been the first-line therapy for many years to treat acute myeloid leukemia (AML). Although this treatment induces complete remissions in the majority of patients, many face a relapse (adaptive resistance) or have refractory disease (primary resistance). Moreover, older patients are often unfit for cytotoxic-based treatment. AML relapse is due to the survival of therapy-resistant leukemia cells (minimal residual disease, MRD). Leukemia cells with stem cell features, named leukemic stem cells (LSCs), residing within MRD are thought to be at the origin of relapse initiation. It is increasingly recognized that leukemia “persisters” are caused by intra-leukemic heterogeneity and non-genetic factors leading to plasticity in therapy response. The BCL2 inhibitor venetoclax, combined with hypomethylating agents or low dose cytarabine, represents an important new therapy especially for older AML patients. However, often there is also a small population of AML cells refractory to venetoclax treatment. As AML MRD reflects the sum of therapy resistance mechanisms, the different faces of treatment “persisters” and LSCs might be exploited to reach an optimal therapy response and prevent the initiation of relapse. Here, we describe the different epigenetic, transcriptional, and metabolic states of therapy sensitive and resistant AML (stem) cell populations and LSCs, how these cell states are influenced by the microenvironment and affect treatment outcome of AML. Moreover, we discuss potential strategies to target dynamic treatment resistance and LSCs.
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影响因子：
28.2
作者：
Cai SF;Chu SH;Goldberg AD;Parvin S;Koche RP;Glass JL;Stein EM;Tallman MS;Sen F;Famulare CA;Cusan M;Huang CH;Chen CW;Zou L;Cordner KB;DelGaudio NL;Durani V;Kini M;Rex M;Tian HS;Zuber J;Baslan T;Lowe SW;Rienhoff HY Jr;Letai A;Levine RL;Armstrong SA
通讯作者：
Armstrong SA
影响因子：
50.3
作者：
Abdel-Wahab O;Adli M;LaFave LM;Gao J;Hricik T;Shih AH;Pandey S;Patel JP;Chung YR;Koche R;Perna F;Zhao X;Taylor JE;Park CY;Carroll M;Melnick A;Nimer SD;Jaffe JD;Aifantis I;Bernstein BE;Levine RL
通讯作者：
Levine RL
影响因子：
82.9
作者：
Eppert, Kolja;Takenaka, Katsuto;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
50.3
作者：
Ebinger S;Özdemir EZ;Ziegenhain C;Tiedt S;Castro Alves C;Grunert M;Dworzak M;Lutz C;Turati VA;Enver T;Horny HP;Sotlar K;Parekh S;Spiekermann K;Hiddemann W;Schepers A;Polzer B;Kirsch S;Hoffmann M;Knapp B;Hasenauer J;Pfeifer H;Panzer-Grümayer R;Enard W;Gires O;Jeremias I
通讯作者：
Jeremias I
影响因子：
8.8
作者：
Carey A;Edwards DK 5th;Eide CA;Newell L;Traer E;Medeiros BC;Pollyea DA;Deininger MW;Collins RH;Tyner JW;Druker BJ;Bagby GC;McWeeney SK;Agarwal A
通讯作者：
Agarwal A