Open Access

Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells

  • Authors:
    • Sana Usmani
    • Urmila Sivagnanalingam
    • Olena Tkachenko
    • Leti Nunez
    • Jessica C. Shand
    • Craig A. Mullen
  • View Affiliations

  • Published online on: March 22, 2019     https://doi.org/10.3892/ol.2019.10188
  • Pages: 5039-5049
  • Copyright: © Usmani et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The present report describes work examining the manner in which nonmalignant bone marrow stromal cells prevent acute lymphoblastic leukemia (ALL) cell death. The initial focus was on the role of stromal cell‑derived C‑X‑C motif chemokine 12 (CXCL12). Interference with CXCL12 production by stroma or blockade of its interactions with ALL by plerixafor did increase ALL cell death and in sensitive ALLs there was synergistic effect with conventional chemotherapy drugs. However, in contrast to most reports, there was considerable heterogeneity regarding the effect between 7 unique primary ALLs, with several exhibiting no sensitivity to CXCL12 blockade. The diversity in effect was not explained by differences in the expression of ALL cell surface receptors for CXCL12. The modest and variable effects of interference with CXCL12 on ALL led to the assessment of gene expression profiles of stromal cells and ALL cells. Gene set enrichment analysis identified pathways associated with metabolism and redox reactions as potentially important in the stromal cell: leukemia cell interaction. Exploratory imaging studies demonstrated bidirectional transfer of intracellular calcien‑labelled molecules and also bidirectional transfer of mitochondria between stromal cells and ALL cells, providing potential means of metabolic interdependence of stromal cells and ALL cells.

References

1 

Shahrabi S, Rezaeeyan H, Ahmadzadeh A, Shahjahani M and Saki N: Bone marrow blood vessels: Normal and neoplastic niche. Oncol Rev. 10:3062016. View Article : Google Scholar : PubMed/NCBI

2 

Ramasamy SK: Structure and Functions of Blood Vessels and Vascular Niches in Bone. Stem Cells Int. 2017:50469532017. View Article : Google Scholar : PubMed/NCBI

3 

Manabe A, Coustan-Smith E, Behm FG, Raimondi SC and Campana D: Bone marrow-derived stromal cells prevent apoptotic cell death in B-lineage acute lymphoblastic leukemia. Blood. 79:2370–2377. 1992.PubMed/NCBI

4 

Manabe A, Murti KG, Coustan-Smith E, Kumagai M, Behm FG, Raimondi SC and Campana D: Adhesion-dependent survival of normal and leukemic human B lymphoblasts on bone marrow stromal cells. Blood. 83:758–766. 1994.PubMed/NCBI

5 

Dominici M, Le Blanc K, Mueller I, Slaper-Cortenbach I, Marini F, Krause D, Deans R, Keating A, Prockop DJ and Horwitz E: Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy. 8:315–317. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Glodek AM, Le Y, Dykxhoorn DM, Park SY, Mostoslavsky G, Mulligan R, Lieberman J, Beggs HE, Honczarenko M and Silberstein LE: Focal adhesion kinase is required for CXCL12-induced chemotactic and pro-adhesive responses in hematopoietic precursor cells. Leukemia. 21:1723–1732. 2007. View Article : Google Scholar : PubMed/NCBI

7 

Acharya M, Edkins AL, Ozanne BW and Cushley W: SDF-1 and PDGF enhance alphavbeta5-mediated ERK activation and adhesion-independent growth of human pre-B cell lines. Leukemia. 23:1807–1817. 2009. View Article : Google Scholar : PubMed/NCBI

8 

Arnaud MP, Vallée A, Robert G, Bonneau J, Leroy C, Varin-Blank N, Rio AG, Troadec MB, Galibert MD and Gandemer V: CD9, a key actor in the dissemination of lymphoblastic leukemia, modulating CXCR4-mediated migration via RAC1 signaling. Blood. 126:1802–1812. 2015. View Article : Google Scholar : PubMed/NCBI

9 

Shen N, Ffrench P, Guyotat D, Ffrench M, Fiere D, Bryon PA and Dechavanne M: Expression of adhesion molecules in endothelial cells during allogeneic bone marrow transplantation. Eur J Haematol. 52:296–301. 1994. View Article : Google Scholar : PubMed/NCBI

10 

Mihara K, Imai C, Coustan-Smith E, Dome JS, Dominici M, Vanin E and Campana D: Development and functional characterization of human bone marrow mesenchymal cells immortalized by enforced expression of telomerase. Br J Haematol. 120:846–849. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Roecklein BA and Torok-Storb B: Functionally distinct human marrow stromal cell lines immortalized by transduction with the human papilloma virus E6/E7 genes. Blood. 85:997–1005. 1995.PubMed/NCBI

12 

Greco WR, Bravo G and Parsons JC: The search for synergy: A critical review from a response surface perspective. Pharmacol Rev. 47:331–385. 1995.PubMed/NCBI

13 

To LB, Levesque JP and Herbert KE: How I treat patients who mobilize hematopoietic stem cells poorly. Blood. 118:4530–4540. 2011. View Article : Google Scholar : PubMed/NCBI

14 

Fricker SP: Physiology and pharmacology of plerixafor. Transfus Med Hemother. 40:237–245. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Sánchez-Martín L, Sánchez-Mateos P and Cabañas C: CXCR7 impact on CXCL12 biology and disease. Trends Mol Med. 19:12–22. 2013. View Article : Google Scholar : PubMed/NCBI

16 

Asri A, Sabour J, Atashi A and Soleimani M: Homing in hematopoietic stem cells: Focus on regulatory role of CXCR7 on SDF1a/CXCR4 axis. EXCLI J. 15:134–143. 2016.PubMed/NCBI

17 

Sison EA, Rau RE, McIntyre E, Li L, Small D and Brown P: MLL-rearranged acute lymphoblastic leukaemia stem cell interactions with bone marrow stroma promote survival and therapeutic resistance that can be overcome with CXCR4 antagonism. Br J Haematol. 160:785–797. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Nishii K, Katayama N, Miwa H, Shikami M, Masuya M, Shiku H and Kita K: Survival of human leukaemic B-cell precursors is supported by stromal cells and cytokines: Association with the expression of bcl-2 protein. Br J Haematol. 105:701–710. 1999. View Article : Google Scholar : PubMed/NCBI

19 

Juarez J, Bradstock KF, Gottlieb DJ and Bendall LJ: Effects of inhibitors of the chemokine receptor CXCR4 on acute lymphoblastic leukemia cells in vitro. Leukemia. 17:1294–1300. 2003. View Article : Google Scholar : PubMed/NCBI

20 

Welschinger R, Liedtke F, Basnett J, Dela Pena A, Juarez JG, Bradstock KF and Bendall LJ: Plerixafor (AMD3100) induces prolonged mobilization of acute lymphoblastic leukemia cells and increases the proportion of cycling cells in the blood in mice. Exp Hematol. 41:293–302, e291. 2013. View Article : Google Scholar : PubMed/NCBI

21 

Sison EA, Magoon D, Li L, Annesley CE, Rau RE, Small D and Brown P: Plerixafor as a chemosensitizing agent in pediatric acute lymphoblastic leukemia: Efficacy and potential mechanisms of resistance to CXCR4 inhibition. Oncotarget. 5:8947–8958. 2014. View Article : Google Scholar : PubMed/NCBI

22 

Sison EA, Magoon D, Li L, Annesley CE, Romagnoli B, Douglas GJ, Tuffin G, Zimmermann J and Brown P: POL5551, a novel and potent CXCR4 antagonist, enhances sensitivity to chemotherapy in pediatric ALL. Oncotarget. 6:30902–30918. 2015. View Article : Google Scholar : PubMed/NCBI

23 

Randhawa S, Cho BS, Ghosh D, Sivina M, Koehrer S, Müschen M, Peled A, Davis RE, Konopleva M and Burger JA: Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia. Br J Haematol. 174:425–436. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Cooper TM, Sison EAR, Baker SD, Li L, Ahmed A, Trippett T, Gore L, Macy ME, Narendran A, August K, et al: A phase 1 study of the CXCR4 antagonist plerixafor in combination with high-dose cytarabine and etoposide in children with relapsed or refractory acute leukemias or myelodysplastic syndrome: A Pediatric Oncology Experimental Therapeutics Investigators' Consortium study (POE 10-03). Pediatr Blood Cancer. doi.10.1002/pbc.26414.

25 

Anthony BA and Link DC: Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol. 35:32–37. 2014. View Article : Google Scholar : PubMed/NCBI

26 

Karpova D and Bonig H: Concise Review: CXCR4/CXCL12 signaling in immature hematopoiesis-lessons from pharmacological and genetic models. Stem Cells. 33:2391–2399. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Gomes AC and Gomes MS: Hematopoietic niches, erythropoiesis and anemia of chronic infection. Exp Hematol. 44:85–91. 2016. View Article : Google Scholar : PubMed/NCBI

28 

Rustom A, Saffrich R, Markovic I, Walther P and Gerdes HH: Nanotubular highways for intercellular organelle transport. Science. 303:1007–1010. 2004. View Article : Google Scholar : PubMed/NCBI

29 

Spees JL, Olson SD, Whitney MJ and Prockop DJ: Mitochondrial transfer between cells can rescue aerobic respiration. Proc Natl Acad Sci USA. 103:1283–1288. 2006. View Article : Google Scholar : PubMed/NCBI

30 

Wang X and Gerdes HH: Transfer of mitochondria via tunneling nanotubes rescues apoptotic PC12 cells. Cell Death Differ. 22:1181–1191. 2015. View Article : Google Scholar : PubMed/NCBI

31 

Lou E, Fujisawa S, Morozov A, Barlas A, Romin Y, Dogan Y, Gholami S, Moreira AL, Manova-Todorova K and Moore MA: Tunneling nanotubes provide a unique conduit for intercellular transfer of cellular contents in human malignant pleural mesothelioma. PLoS One. 7:e330932012. View Article : Google Scholar : PubMed/NCBI

32 

Pasquier J, Guerrouahen BS, Al Thawadi H, Ghiabi P, Maleki M, Abu-Kaoud N, Jacob A, Mirshahi M, Galas L, Rafii S, et al: Preferential transfer of mitochondria from endothelial to cancer cells through tunneling nanotubes modulates chemoresistance. J Transl Med. 11:942013. View Article : Google Scholar : PubMed/NCBI

33 

Moschoi R, Imbert V, Nebout M, Chiche J, Mary D, Prebet T, Saland E, Castellano R, Pouyet L, Collette Y, et al: Protective mitochondrial transfer from bone marrow stromal cells to acute myeloid leukemic cells during chemotherapy. Blood. 128:253–264. 2016. View Article : Google Scholar : PubMed/NCBI

34 

Marlein CR, Zaitseva L, Piddock RE, Robinson SD, Edwards DR, Shafat MS, Zhou Z, Lawes M, Bowles KM and Rushworth SA: NADPH oxidase-2 derived superoxide drives mitochondrial transfer from bone marrow stromal cells to leukemic blasts. Blood. 130:1649–1660. 2017.PubMed/NCBI

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June 2019
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Copy and paste a formatted citation
APA
Usmani, S., Sivagnanalingam, U., Tkachenko, O., Nunez, L., Shand, J.C., & Mullen, C.A. (2019). Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells. Oncology Letters, 17, 5039-5049. https://doi.org/10.3892/ol.2019.10188
MLA
Usmani, S., Sivagnanalingam, U., Tkachenko, O., Nunez, L., Shand, J. C., Mullen, C. A."Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells". Oncology Letters 17.6 (2019): 5039-5049.
Chicago
Usmani, S., Sivagnanalingam, U., Tkachenko, O., Nunez, L., Shand, J. C., Mullen, C. A."Support of acute lymphoblastic leukemia cells by nonmalignant bone marrow stromal cells". Oncology Letters 17, no. 6 (2019): 5039-5049. https://doi.org/10.3892/ol.2019.10188