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CHRONIC MYELOGENOUS LEUKEMIA

Spred1 deficit promotes treatment resistance and transformation of chronic phase CML

Leukemia volume 36, pages 492–506 (2022)Cite this article

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Abstract

Spred1 is highly expressed in normal hematopoietic stem cells (HSCs). Lack of Spred1 function has been associated with aberrant hematopoiesis and acute leukemias. In chronic myelogenous leukemia (CML), Spred1 is reduced in patients with accelerated phase (AP) or blast crisis (BC) CML, thereby suggesting that deficit of this protein may contribute to disease transformation. In fact, Spred1 knockout (KO) in SCLtTA/BCR-ABL CML mice either globally, or restricted to hematopoietic cells (i.e., HSCs) or to endothelial cells (ECs), led to transformation of chronic phase (CP) CML into AP/BC CML. Upon BCR-ABL induction, all three Spred1 KO CML models showed AP/BC features. However, compared with global Spred1 KO, the AP/BC phenotypes of HSC-Spred1 KO and EC-Spred1 KO CML models were attenuated, suggesting a concurrent contribution of Spred1 deficit in multiple compartments of the leukemic bone marrow niche to the CML transformation. Spred1 KO, regardless if occurred in HSCs or in ECs, increased miR-126 in LSKs (Lin−Sca-1+c-Kit+), a population enriched in leukemic stem cells (LSCs), resulting in expansion of LSCs, likely through hyperactivation of the MAPK/ERK pathway that augmented Bcl-2 expression and stability. This ultimately led to enhancement of Bcl-2-dependent oxidative phosphorylation that supported homeostasis, survival and activity of LSCs and drove AP/BC transformation.

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Fig. 1: Downregulation of Spred1 was observed in BM and CD34+ cells from patients with BC CML and associated with an increased “stemness” phenotype.
Fig. 2: Spred1 deficit promotes CML transformation.
Fig. 3: BM or LSK cells from Spred1 KO CML mice recapitulated AP/BC phenotype in recipient mice.
Fig. 4: Spred1 insufficiency in HSCs caused an attenuated CML transformation phenotype.
Fig. 5: SPRED1 KO in ECs increases arterioles in the BM niche.
Fig. 6: Spred1 loss in the BM vascular niche independently contributes to CML transformation.
Fig. 7: Spred1 loss in the BM vascular niche independently contributes to CML transformation.
Fig. 8: Spred1 depletion promotes TKI resistance in CML.

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Availability of data and materials

RNA sequencing data produced in our laboratory and analysed in this study are available at the Gene Expression Omnibus (GEO) repository of the National Center for Biotechnology Information (GSE181589). Supplementary Information including Supplementary Fig. 1–12 and Supplementary Table 1 are provided with the online version of this paper. All other datasets generated during this study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was supported in part by National Cancer Institute grants: CA248475 (GM/BZ), CA205247 (YHK/GM), CA201184 (GM), CA25004467 (RCR/YHK/GM), the Gehr Family Foundation (GM), the George Hoag Family Foundation (GM), International Program for Ph.D. Candidates (Sun Yat-Sen University, China), JSPS KAKENHI (S) JP17H06175 and AMED-CREST JP 20gm1110009 (AY). We are grateful to Marjorie Robbins for editing the manuscript. We acknowledge the support of the Animal Resources Center, Analytical Cytometry, Pathology (Hematopoietic Tissue Biorepository), Light Microscopy, and DNA/RNA Cores at City of Hope Comprehensive Cancer Center supported by the National Cancer Institute of the National Institutes of Health under award number P30CA33572. We are grateful to COH Comprehensive Cancer Center, the patients, and their physicians for providing primary patient material for this study.

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  1. These author contributed equally: Junjing Qiao, Chen Liang, Dandan Zhao.

Authors and Affiliations

  1. Department of Pathology, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, Guangdong, P. R. China

    Junjing Qiao & Anjia Han

  2. Department of Hematological Malignancies Translational Science, Gehr Family Center for Leukemia Research, City of Hope Medical Center and Beckman Research Institute, Duarte, CA, USA

    Junjing Qiao, Chen Liang, Dandan Zhao, Le Xuan Truong Nguyen, Fang Chen, Shanshan Suo, Dinh Hoa Hoang, Ivan Rodriguez Rodriguez, Yasmin Elhajmoussa, Lucy Ghoda, Anthony S. Stein, Haris Ali, Paul Koller, Bin (Amber) Zhang & Guido Marcucci

  3. Phase I Clinical Research Center, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan, P. R. China

    Junjing Qiao

  4. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, P. R. China

    Chen Liang

  5. Department of Hematology, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang, P. R. China

    Shanshan Suo

  6. Paul O’ Gorman Leukemia Research Centre, College of Medical, Veterinary and Life Sciences, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK

    Francesca Pellicano & Mhairi Copland

  7. Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo, Japan

    Akihiko Yoshimura

  8. University of Maryland, Baltimore, MD, USA

    Danilo Perrotti

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Contributions

JQ designed and conducted experiments, analyzed data, wrote the manuscript; CL, DZ and L.X.T.N designed and conducted experiments and analyzed data; FC, SS, DHH, FP, IRR and YE conducted experiments; LG provided patient samples; AY provided Spred1 KO and Spred1flox/flox mice and reviewed the manuscript; AS, HA, PK, and DP reviewed data and the manuscript; MC and AH reviewed data and the manuscript and provided administrative support; BZ and GM designed experiments, analyzed data, wrote manuscript and provided administrative support.

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Correspondence to Anjia Han, Bin (Amber) Zhang or Guido Marcucci.

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Patient sample acquisition was approved by the Institutional Review Boards (IRB) at the COHNMC, in accordance with an assurance filed with and approved by the Department of Health and Human Services and met all requirements of the Declaration of Helsinki. CML patients were consented on the IRB #18067 protocol.

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Qiao, J., Liang, C., Zhao, D. et al. Spred1 deficit promotes treatment resistance and transformation of chronic phase CML. Leukemia 36, 492–506 (2022). https://doi.org/10.1038/s41375-021-01423-x

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