Single-cell analysis reveals the chemotherapy-induced cellular reprogramming and novel therapeutic targets in relapsed/refractory acute myeloid leukemia.
Single-cell analysis reveals the chemotherapy-induced cellular reprogramming and novel therapeutic targets in relapsed/refractory acute myeloid leukemia.
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单细胞分析揭示化疗诱导的细胞重编程和复发/难治性急性髓系白血病的新治疗靶点
DOI：
10.1038/s41375-022-01789-6
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发表时间：
2023-02
期刊：
影响因子：
11.4
通讯作者：
Qian, Sixuan
中科院分区：
文献类型：
--
作者：
Li, Kening;Du, Yuxin;Cai, Yun;Liu, Wenjie;Lv, Yan;Huang, Bin;Zhang, Lishen;Wang, Zhi;Liu, Ping;Sun, Qian;Li, Ning;Zhu, Mengyan;Bosco, Bakwatanisa;Li, Liangyu;Wu, Wei;Wu, Lingxiang;Li, Jianyong;Wang, Qianghu;Hong, Ming;Qian, Sixuan
耐药性和复发是AML相关死亡的主要原因。利用单细胞RNA测序（scRNA-seq），我们分析了原发性难治性或短期复发性AML患者骨髓样本的细胞状态，并定义了转录的肿瘤内异质性。我们发现，与增殖的干/祖细胞样细胞（PSP）相比，静止的干细胞样细胞（QSC）亚群参与了AML的化疗耐药性和不良结局。通过进行纵向scRNA-seq分析，我们证明了PSP在难治性AML患者化疗期间被重编程以获得QSC样表达模式，其特征在于CD 52和LGALS 1表达上调。流式细胞术分析进一步证实，诊断时预先存在的CD 99 + CD 49 d + CD 52+半乳糖凝集素-1+（QSC）细胞与化疗耐药性相关，这些细胞进一步富集在难治性患者的残留AML细胞中。QSC和单核细胞之间的CD 52-SIGLEC 10相互作用可能导致免疫逃避和不良结局。此外，我们发现LGALS 1是化疗耐药AML的一个有希望的靶点，LGALS 1抑制剂可以帮助消除QSC并增强患者来源的原代AML细胞，细胞系和AML异种移植模型中的化疗。我们的研究结果将有助于更好地了解AML化疗耐药机制，并为复发/难治性AML患者开发新的治疗策略。
Chemoresistance and relapse are the leading cause of AML-related deaths. Utilizing single-cell RNA sequencing (scRNA-seq), we dissected the cellular states of bone marrow samples from primary refractory or short-term relapsed AML patients and defined the transcriptional intratumoral heterogeneity. We found that compared to proliferating stem/progenitor-like cells (PSPs), a subpopulation of quiescent stem-like cells (QSCs) were involved in the chemoresistance and poor outcomes of AML. By performing longitudinal scRNA-seq analyses, we demonstrated that PSPs were reprogrammed to obtain a QSC-like expression pattern during chemotherapy in refractory AML patients, characterized by the upregulation of CD52 and LGALS1 expression. Flow cytometric analysis further confirmed that the preexisting CD99+CD49d+CD52+Galectin-1+ (QSCs) cells at diagnosis were associated with chemoresistance, and these cells were further enriched in the residual AML cells of refractory patients. Interaction of CD52-SIGLEC10 between QSCs and monocytes may contribute to immune evading and poor outcomes. Furthermore, we identified that LGALS1 was a promising target for chemoresistant AML, and LGALS1 inhibitor could help eliminate QSCs and enhance the chemotherapy in patient-derived primary AML cells, cell lines, and AML xenograft models. Our results will facilitate a better understanding of the AML chemoresistance mechanism and the development of novel therapeutic strategies for relapsed/refractory AML patients.
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DOI：
10.1073/pnas.1808790115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Bausch-Fluck D;Goldmann U;Müller S;van Oostrum M;Müller M;Schubert OT;Wollscheid B
通讯作者：
Wollscheid B
影响因子：
82.9
作者：
Li S;Garrett-Bakelman FE;Chung SS;Sanders MA;Hricik T;Rapaport F;Patel J;Dillon R;Vijay P;Brown AL;Perl AE;Cannon J;Bullinger L;Luger S;Becker M;Lewis ID;To LB;Delwel R;Löwenberg B;Döhner H;Döhner K;Guzman ML;Hassane DC;Roboz GJ;Grimwade D;Valk PJ;D'Andrea RJ;Carroll M;Park CY;Neuberg D;Levine R;Melnick AM;Mason CE
通讯作者：
Mason CE
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：
Lechman ER;Gentner B;Ng SW;Schoof EM;van Galen P;Kennedy JA;Nucera S;Ciceri F;Kaufmann KB;Takayama N;Dobson SM;Trotman-Grant A;Krivdova G;Elzinga J;Mitchell A;Nilsson B;Hermans KG;Eppert K;Marke R;Isserlin R;Voisin V;Bader GD;Zandstra PW;Golub TR;Ebert BL;Lu J;Minden M;Wang JC;Naldini L;Dick JE
通讯作者：
Dick JE
影响因子：
28.2
作者：
Duy C;Li M;Teater M;Meydan C;Garrett-Bakelman FE;Lee TC;Chin CR;Durmaz C;Kawabata KC;Dhimolea E;Mitsiades CS;Doehner H;D'Andrea RJ;Becker MW;Paietta EM;Mason CE;Carroll M;Melnick AM
通讯作者：
Melnick AM