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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2018

Open Access 01-12-2018 | Research

Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia

Authors: Chao Tang, Ming-Hao Li, Ya-Li Chen, Hui-Ying Sun, Sheng-Li Liu, Wei-Wei Zheng, Meng-Yi Zhang, Hui Li, Wei Fu, Wen-Jun Zhang, Ai-Bin Liang, Zhong-Hua Tang, Deng-Li Hong, Bin-Bing S. Zhou, Cai-Wen Duan

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2018

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Abstract

Background

Considerable efforts have been devoted toward the uncovering of the molecular mechanisms underlying the maintenance of hematopoietic stem cells (HSCs) by the normal bone marrow (BM) niche. Previously, we demonstrated that a chemotherapy-induced niche, which is mainly composed of mesenchymal stem cells (MSCs), protects the residual B-cell acute lymphoblastic leukemia (B-ALL) cells from the insult of chemotherapeutic drugs. However, the roles of chemotherapy-induced niche on HSCs functions in B-ALL remain unclear.

Methods

We established an oncogenic N-MYC-driven B-ALL mouse model, which were subsequently treated with common chemotherapy drug cytarabine (Ara-C) and daunorubicin (DNR). After treatment, the structures of the BM niche were imaged by immunofluorescence staining. Then, the self-renewal and differentiation capability of the MSCs in the BM after Ara-C and DNR treatment were studied by ex vivo culture and gene expression analysis with RNA-seq and qRT-PCR. The effects of chemotherapy-induced niche on the hematopoietic reconstitution of HSCs were determined with series transplantation assay. Furthermore, the cell cycle, ROS level, mitochondrial membrane potential and cell apoptosis of HSCs were detected by flow cytometry.

Results

The MSCs, which is the main component of chemotherapy-induced BM niche, have decreased self-renewal capability and are prone to differentiate into adipocytes and chondrocytes. The results of gene expression analysis with RNA-seq showed that the MSCs have reduced levels of cytokines, including SCF, CXCL12, ANGPT1, VCAM1, and IL7. Furthermore, the chemotherapy-induced niche perturbed the hematopoietic reconstitution of HSCs in our N-MYC-driven B-ALL mouse model by promoting HSCs to enter cell cycle and increasing intracellular ROS levels and mitochondrial membrane potential of HSCs, which lead to the cell apoptosis of HSCs.

Conclusions

Chemotherapy-induced BM niche perturbs the hematopoietic reconstitution of HSCs by increasing intracellular ROS level and inducing cell apoptosis.
Appendix
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Literature
1.
2.
Doulatov S, Notta F, Laurenti E, Dick JE. Hematopoiesis: a human perspective. Cell Stem Cell. 2012;10(2):120–36.CrossRefPubMed
3.
Cabezas-Wallscheid N, Buettner F, Sommerkamp P, Klimmeck D, Ladel L, Thalheimer FB, Pastor-Flores D, Roma LP, Renders S, Zeisberger P, et al. Vitamin A-retinoic acid signaling regulates hematopoietic stem cell dormancy. Cell. 2017;169(5):807–23. e819CrossRefPubMed
4.
Haas R, Mohle R, Fruhauf S, Goldschmidt H, Witt B, Flentje M, Wannenmacher M, Hunstein W. Patient characteristics associated with successful mobilizing and autografting of peripheral blood progenitor cells in malignant lymphoma. Blood. 1994;83(12):3787–94.PubMed
5.
Elmaagacli AH, Koldehoff M, Steckel NK, Trenschel R, Ottinger H, Beelen DW. Cytochrome P450 2C19 loss-of-function polymorphism is associated with an increased treatment-related mortality in patients undergoing allogeneic transplantation. Bone Marrow Transplant. 2007;40(7):659–64.CrossRefPubMed
6.
Wang Y, Probin V, Zhou D. Cancer therapy-induced residual bone marrow injury-mechanisms of induction and implication for therapy. Curr Cancer Ther Rev. 2006;2(3):271–9.CrossRefPubMedPubMedCentral
7.
To LB, Levesque JP, Herbert KE. How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 2011;118(17):4530–40.CrossRefPubMed
8.
Crane GM, Jeffery E, Morrison SJ. Adult haematopoietic stem cell niches. Nat Rev Immunol. 2017;17(9):573–90.CrossRefPubMed
9.
10.
Kunisaki Y, Bruns I, Scheiermann C, Ahmed J, Pinho S, Zhang D, Mizoguchi T, Wei Q, Lucas D, Ito K, et al. Arteriolar niches maintain haematopoietic stem cell quiescence. Nature. 2013;502(7473):637–43.CrossRefPubMedPubMedCentral
11.
Acar M, Kocherlakota KS, Murphy MM, Peyer JG, Oguro H, Inra CN, Jaiyeola C, Zhao Z, Luby-Phelps K, Morrison SJ. Deep imaging of bone marrow shows non-dividing stem cells are mainly perisinusoidal. Nature. 2015;526(7571):126–30.CrossRefPubMedPubMedCentral
12.
13.
Crawford J, Dale DC, Lyman GH. Chemotherapy-induced neutropenia: risks, consequences, and new directions for its management. Cancer. 2004;100(2):228–37.CrossRefPubMed
14.
Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, Vora A, Baruchel A, Silverman LB, Schmiegelow K, et al. Childhood acute lymphoblastic leukemia: progress through collaboration. J Clin Oncol. 2015;33(27):2938–48.CrossRefPubMedPubMedCentral
15.
Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, Zhou XC, Cai YJ, Li ZQ, Zhang F, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25(6):778–93.CrossRefPubMed
16.
Sugihara E, Shimizu T, Kojima K, Onishi N, Kai K, Ishizawa J, Nagata K, Hashimoto N, Honda H, Kanno M, et al. Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor. Oncogene. 2012;31(23):2849–61.CrossRefPubMed
17.
Kusumbe AP, Ramasamy SK, Starsichova A, Adams RH. Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue. Nat Protoc. 2015;10(12):1904–14.CrossRefPubMed
18.
Pinho S, Lacombe J, Hanoun M, Mizoguchi T, Bruns I, Kunisaki Y, Frenette PS. PDGFRalpha and CD51 mark human nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp Med. 2013;210(7):1351–67.CrossRefPubMedPubMedCentral
19.
Wilson A, Laurenti E, Oser G, van der Wath RC, Blanco-Bose W, Jaworski M, Offner S, Dunant CF, Eshkind L, Bockamp E, et al. Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair. Cell. 2008;135(6):1118–29.CrossRefPubMed
20.
Kiel MJ, Yilmaz OH, Iwashita T, Terhorst C, Morrison SJ. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell. 2005;121(7):1109–21.CrossRefPubMed
21.
22.
Ito K, Hirao A, Arai F, Takubo K, Matsuoka S, Miyamoto K, Ohmura M, Naka K, Hosokawa K, Ikeda Y, et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med. 2006;12(4):446–51.CrossRefPubMed
23.
Kemp K, Morse R, Wexler S, Cox C, Mallam E, Hows J, Donaldson C. Chemotherapy-induced mesenchymal stem cell damage in patients with hematological malignancy. Ann Hematol. 2010;89(7):701–13.CrossRefPubMed
24.
Lucas D, Scheiermann C, Chow A, Kunisaki Y, Bruns I, Barrick C, Tessarollo L, Frenette PS. Chemotherapy-induced bone marrow nerve injury impairs hematopoietic regeneration. Nat Med. 2013;19(6):695–703.CrossRefPubMedPubMedCentral
25.
26.
Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, Nagasawa T, Link DC. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227–30.CrossRefPubMedPubMedCentral
27.
Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell. 2004;118(2):149–61.CrossRefPubMed
28.
Goncalves KA, Silberstein L, Li S, Severe N, Hu MG, Yang H, Scadden DT, Hu GF. Angiogenin promotes hematopoietic regeneration by dichotomously regulating quiescence of stem and progenitor cells. Cell. 2016;166(4):894–906.CrossRefPubMedPubMedCentral
29.
30.
Suda T, Takubo K, Semenza GL. Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell. 2011;9(4):298–310.CrossRefPubMed
31.
Bisi JE, Sorrentino JA, Roberts PJ, Tavares FX, Strum JC. Preclinical characterization of G1T28: a novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol Cancer Ther. 2016;15(5):783–93.CrossRefPubMed
32.
He S, Roberts PJ, Sorrentino JA, Bisi JE, Storrie-White H, Tiessen RG, Makhuli KM, Wargin WA, Tadema H, van Hoogdalem EJ, et al. Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med. 2017;9(387). https://​doi.​org/​10.​1126/​scitranslmed.​aal3986.
Metadata
Title
Chemotherapy-induced niche perturbs hematopoietic reconstitution in B-cell acute lymphoblastic leukemia
Authors
Chao Tang
Ming-Hao Li
Ya-Li Chen
Hui-Ying Sun
Sheng-Li Liu
Wei-Wei Zheng
Meng-Yi Zhang
Hui Li
Wei Fu
Wen-Jun Zhang
Ai-Bin Liang
Zhong-Hua Tang
Deng-Li Hong
Bin-Bing S. Zhou
Cai-Wen Duan
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2018
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-018-0859-3

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