Research Paper Volume 12, Issue 24 pp 25337—25355

Single cell sequencing reveals cell populations that predict primary resistance to imatinib in chronic myeloid leukemia

Weilong Zhang1,2, *, , Beibei Yang2, *, , Linqian Weng3, , Jiangtao Li3, , Jiefei Bai3, , Ting Wang3, , Jingwen Wang4, , Jin Ye4, , Hongmei Jing1, , Yuchen Jiao2, , Xixi Chen5,6, , Hui Liu3, , Yi-Xin Zeng2,7, ,

  • 1 Department of Hematology, Lymphoma Research Center, Peking University Third Hospital, Beijing 100191, China
  • 2 State Key Lab of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
  • 3 Department of Hematology, Beijing Hospital, National Center of Gerontology, Beijing, China
  • 4 Department of Hematology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
  • 5 Genetron Health (Beijing) Co. Ltd., Beijing 102206, China
  • 6 Children’s Hospital of Chongqing Medical University, Chongqing 400014, China
  • 7 Department of Experimental Research, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in Southern China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong Province, China
* Equal contribution

Received: June 6, 2020       Accepted: September 20, 2020       Published: November 23, 2020
How to Cite

Copyright: © 2020 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


The treatment of chronic myeloid leukemia (CML), a disease caused by t(9;22)(q34;q11) reciprocal translocation, has advanced largely through the use of targeted tyrosine kinase inhibitors (TKIs). To identify molecular differences that might distinguish TKI responders from non-responders, we performed single cell RNA sequencing on cells (n = 41,723 cells) obtained from the peripheral blood of four CML patients at different stages of treatment to generate single cell expression profiles. Analysis of our single cell expression profiles in conjunction with those previously obtained from the bone marrow of additional CML patients and healthy donors (total = 69,263 cells) demonstrated that imatinib treatment significantly altered leukocyte population compositions in both responders and non-responders, and affected the expression profiles of multiple cell populations, including non-neoplastic cell types. Notably, in imatinib poor-responders, patient-specific pre-treatment unique stem/progenitor cells became enriched in peripheral blood compared to the responders. These results indicate that resistance to TKIs might be intrinsic in some CML patients rather than acquired, and that non-neoplastic immune cell types may also play vital roles in dispersing the responsiveness of patients to TKIs. Furthermore, these results demonstrated the potential utility of peripheral blood as a diagnostic tool in the TKI sensitivity of CML patients.


CML: chronic myeloid leukemia; TKI: tyrosine kinase inhibitor; PBMC: peripheral blood mononuclear cell; CCA: canonical correlation analysis; PCA: principle component analysis; KNN: K-nearest neighbors; MNN: mutual nearest neighbors; tSNE: t-distributed stochastic neighbor embedding; UMAP: uniform manifold approximation and projection; GSEA: gene set enrichment analysis; GSVA: gene set variation analysis; UMI: unique molecular index; HSC: hematopoietic stem cells; CMP: common myeloid progenitors; GMP: granuloid progenitors; MEP: megakaryocyte/erythrocyte progenitors; BM: bone marrow; BC: blast crisis; BT: before treatment; AT: after treatment.