Acute lymphoblastic leukemia

Blocking ATM-dependent NF-κB pathway overcomes niche protection and improves chemotherapy response in acute lymphoblastic leukemia

Abstract

Bone marrow (BM) niche responds to chemotherapy-induced cytokines secreted from acute lymphoblastic leukemia (ALL) cells and protects the residual cells from chemotherapeutics in vivo. However, the underlying molecular mechanisms for the induction of cytokines by chemotherapy remain unknown. Here, we found that chemotherapeutic drugs (e.g., Ara-C, DNR, 6-MP) induced the expression of niche-protecting cytokines (GDF15, CCL3 and CCL4) in both ALL cell lines and primary cells in vitro. The ATM and NF-κB pathways were activated after chemotherapy treatment, and the pharmacological or genetic inhibition of these pathways significantly reversed the cytokine upregulation. Besides, chemotherapy-induced NF-κB activation was dependent on ATM-TRAF6 signaling, and NF-κB transcription factor p65 directly regulated the cytokines expression. Furthermore, we found that both pharmacological and genetic perturbation of ATM and p65 significantly decreased the residual ALL cells after Ara-C treatment in ALL xenograft mouse models. Together, these results demonstrated that ATM-dependent NF-κB activation mediated the cytokines induction by chemotherapy and ALL resistance to chemotherapeutics. Inhibition of ATM-dependent NF-κB pathway can sensitize ALL to chemotherapeutics, providing a new strategy to eradicate residual chemo-resistant ALL cells.

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References

  1. 1.

    Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. 2015;373:1541–52. https://doi.org/10.1056/NEJMra1400972

  2. 2.

    Dinner S, Lee D, Liedtke M. Current therapy and novel agents for relapsed or refractory acute lymphoblastic leukemia. Leuk Lymphoma. 2014;55:1715–24. https://doi.org/10.3109/10428194.2013.856428

  3. 3.

    Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381:1943–55. https://doi.org/10.1016/S0140-6736(12)62187-4

  4. 4.

    Mullighan CG, Phillips LA, Su X, Ma J, Miller CB, Shurtleff SA, et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. 2008;322:1377–80. https://doi.org/10.1126/science.1164266

  5. 5.

    Tzoneva G, Perez-Garcia A, Carpenter Z, Khiabanian H, Tosello V, Allegretta M, et al. Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL. Nat Med. 2013;19:368–71. https://doi.org/10.1038/nm.3078

  6. 6.

    Meyer JA, Wang J, Hogan LE, Yang JJ, Dandekar S, Patel JP, et al. Relapse-specific mutations in NT5C2 in childhood acute lymphoblastic leukemia. Nat Genet. 2013;45:290–4. https://doi.org/10.1038/ng.2558

  7. 7.

    Li B, Li H, Bai Y, Kirschner-Schwabe R, Yang JJ, Chen Y, et al. Negative feedback-defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL. Nat Med. 2015;21:563–71. https://doi.org/10.1038/nm.3840

  8. 8.

    Tzoneva G, Dieck CL, Oshima K, Ambesi-Impiombato A, Sanchez-Martin M, Madubata CJ, et al. Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia. Nature. 2018;553:511–4. https://doi.org/10.1038/nature25186

  9. 9.

    Li L, Neaves WB. Normal stem cells and cancer stem cells: the niche matters. Cancer Res. 2006;66:4553–7. https://doi.org/10.1158/0008-5472.CAN-05-3986

  10. 10.

    David E, Blanchard F, Heymann MF, De Pinieux G, Gouin F, Redini F, et al. The bone niche of chondrosarcoma: a sanctuary for drug resistance, tumour growth and also a source of new therapeutic targets. Sarcoma. 2011;2011:932451. https://doi.org/10.1155/2011/932451

  11. 11.

    Zhao M, Li L. Regulation of hematopoietic stem cells in the niche. Sci China Life Sci. 2015;58:1209–15. https://doi.org/10.1007/s11427-015-4960-y

  12. 12.

    Boulais PE, Frenette PS. Making sense of hematopoietic stem cell niches. Blood. 2015;125:2621–9. https://doi.org/10.1182/blood-2014-09-570192

  13. 13.

    Calvi LM, Link DC. The hematopoietic stem cell niche in homeostasis and disease. Blood. 2015;126:2443–51. https://doi.org/10.1182/blood-2015-07-533588

  14. 14.

    Sanchez-Aguilera A, Mendez-Ferrer S. The hematopoietic stem-cell niche in health and leukemia. Cell Mol Life Sci. 2017;74:579–90. https://doi.org/10.1007/s00018-016-2306-y

  15. 15.

    Watnick RS. The role of the tumor microenvironment in regulating angiogenesis. Cold Spring Harb Perspect Med. 2012;2:a006676. https://doi.org/10.1101/cshperspect.a006676

  16. 16.

    Ribatti D, Vacca A. The role of microenvironment in tumor angiogenesis. Genes Nutr. 2008;3:29–34. https://doi.org/10.1007/s12263-008-0076-3

  17. 17.

    Jung YD, Ahmad SA, Liu W, Reinmuth N, Parikh A, Stoeltzing O, et al. The role of the microenvironment and intercellular cross-talk in tumor angiogenesis. Semin Cancer Biol. 2002;12:105–12. https://doi.org/10.1006/scbi.2001.0418

  18. 18.

    Gilbert LA, Hemann MT. DNA damage-mediated induction of a chemoresistant niche. Cell. 2010;143:355–66. https://doi.org/10.1016/j.cell.2010.09.043

  19. 19.

    Ye H, Adane B, Khan N, Sullivan T, Minhajuddin M, Gasparetto M, et al. Leukemic stem cells evade chemotherapy by metabolic adaptation to an adipose tissue niche. Cell Stem Cell. 2016;19:23–37. https://doi.org/10.1016/j.stem.2016.06.001

  20. 20.

    Duan CW, Shi J, Chen J, Wang B, Yu YH, Qin X, et al. Leukemia propagating cells rebuild an evolving niche in response to therapy. Cancer Cell. 2014;25:778–93. https://doi.org/10.1016/j.ccr.2014.04.015

  21. 21.

    Members BIGDC. The BIG Data Center: from deposition to integration to translation. Nucleic Acids Res. 2017;45(D1):D18–D24. https://doi.org/10.1093/nar/gkw1060

  22. 22.

    Pal D, Blair HJ, Elder A, Dormon K, Rennie KJ, Coleman DJ, et al. Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia. Leukemia. 2016;30:1691–1700. https://doi.org/10.1038/leu.2016.79

  23. 23.

    Jiang Z, Wu D, Ye W, Weng J, Lai P, Shi P, et al. Defined, serum/feeder-free conditions for expansion and drug screening of primary B-acute lymphoblastic leukemia. Oncotarget. 2017;8:106382–92. https://doi.org/10.18632/oncotarget.22466

  24. 24.

    Rodier F, Coppe JP, Patil CK, Hoeijmakers WA, Munoz DP, Raza SR, et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11:973–9. https://doi.org/10.1038/ncb1909

  25. 25.

    Zhou BB, Bartek J. Targeting the checkpoint kinases: chemosensitization versus chemoprotection. Nat Rev Cancer. 2004;4:216–25. https://doi.org/10.1038/nrc1296

  26. 26.

    Golding SE, Rosenberg E, Valerie N, Hussaini I, Frigerio M, Cockcroft XF, et al. Improved ATM kinase inhibitor KU-60019 radiosensitizes glioma cells, compromises insulin, AKT and ERK prosurvival signaling, and inhibits migration and invasion. Mol Cancer Ther. 2009;8:2894–902. https://doi.org/10.1158/1535-7163.MCT-09-0519

  27. 27.

    Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-kappaB as the matchmaker. Nat Immunol. 2011;12:715–23. https://doi.org/10.1038/ni.2060

  28. 28.

    Xia JB, Liu GH, Chen ZY, Mao CZ, Zhou DC, Wu HY, et al. Hypoxia/ischemia promotes CXCL10 expression in cardiac microvascular endothelial cells by NFkB activation. Cytokine. 2016;81:63–70. https://doi.org/10.1016/j.cyto.2016.02.007

  29. 29.

    Hinz M, Stilmann M, Arslan SC, Khanna KK, Dittmar G, Scheidereit C. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. Mol Cell. 2010;40:63–74. https://doi.org/10.1016/j.molcel.2010.09.008

  30. 30.

    Pahl HL. Activators and target genes of Rel/NF-kappaB transcription factors. Oncogene. 1999;18:6853–66. https://doi.org/10.1038/sj.onc.1203239

  31. 31.

    Zhou BB, Elledge SJ. The DNA damage response: putting checkpoints in perspective. Nature. 2000;408:433–9. https://doi.org/10.1038/35044005

  32. 32.

    Khanna KK, Jackson SP. DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet. 2001;27:247–54. https://doi.org/10.1038/85798

  33. 33.

    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8. https://doi.org/10.1038/nature08467

  34. 34.

    Harper JW, Elledge SJ. The DNA damage response: ten years after. Mol Cell. 2007;28:739–45. https://doi.org/10.1016/j.molcel.2007.11.015

  35. 35.

    Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 2015;520:368–72. https://doi.org/10.1038/nature14336

  36. 36.

    Yang DQ, Kastan MB. Participation of ATM in insulin signalling through phosphorylation of eIF-4E-binding protein 1. Nat Cell Biol. 2000;2:893–8. https://doi.org/10.1038/35046542

  37. 37.

    Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-kappaB signaling pathways. Nat Immunol. 2011;12:695–708. https://doi.org/10.1038/ni.2065

  38. 38.

    Santivasi WL, Xia F. Ionizing radiation-induced DNA damage, response, and repair. Antioxid Redox Signal. 2014;21:251–9. https://doi.org/10.1089/ars.2013.5668

  39. 39.

    Karin M. Nuclear factor-kappaB in cancer development and progression. Nature. 2006;441:431–6. https://doi.org/10.1038/nature04870

  40. 40.

    Xu RX, Liu RY, Wu CM, Zhao YS, Li Y, Yao YQ, et al. DNA damage-induced NF-kappaB activation in human glioblastoma cells promotes miR-181b expression and cell proliferation. Cell Physiol Biochem. 2015;35:913–25. https://doi.org/10.1159/000369748

  41. 41.

    Wu ZH, Wong ET, Shi Y, Niu J, Chen Z, Miyamoto S, et al. ATM- and NEMO-dependent ELKS ubiquitination coordinates TAK1-mediated IKK activation in response to genotoxic stress. Mol Cell. 2010;40:75–86. https://doi.org/10.1016/j.molcel.2010.09.010

  42. 42.

    Anthony BA, Link DC. Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol. 2014;35:32–37. https://doi.org/10.1016/j.it.2013.10.002

  43. 43.

    Morrison SJ, Scadden DT. The bone marrow niche for haematopoietic stem cells. Nature. 2014;505:327–34. https://doi.org/10.1038/nature12984

  44. 44.

    Corre J, Labat E, Espagnolle N, Hebraud B, Avet-Loiseau H, Roussel M, et al. Bioactivity and prognostic significance of growth differentiation factor GDF15 secreted by bone marrow mesenchymal stem cells in multiple myeloma. Cancer Res. 2012;72:1395–406. https://doi.org/10.1158/0008-5472.CAN-11-0188

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Acknowledgements

We thank Jian-Min Zhu, Yao Chen and Hou-Shun Fang (Shanghai Children’s Medical Center, Shanghai Jiao Tong University School of Medicine) for excellent technical support. This work is supported by the National Key R&D Program of China, Stem Cell and Translation Research (No. 2016YFA0102000 to C-WD), and the National Natural Science Foundation of China (No. 31530017 to B-BSZ; No. 81570121 to C-WD), and the National Basic Research Program of China (973 program 2015CB553904 to B-BSZ), and Shanghai Science and Technology Development Funds (No. 14411950600 to JC), and the Science and Technology Commission of Pudong District, Shanghai Municipality (No. PKJ2015-Y04 to C-WD), and Innovation Program of Shanghai Municipal Education Commission (No. 15ZZ052 to C-WD), Shanghai Program of Shanghai Academic/Technology Research Leader, Shanghai Municipality (No. 16XD1402100 to B-BSZ), and the Hospital-Public Cross-Link Project of Shanghai Jiao Tong University (No. YG2017MS31 to C-WD).

Author information

Y-LC, CT and M-YZ were the major contributors to experiments and data analysis. B-BSZ, C-WD and H-ZC designed the study, interpreted data, and wrote the paper. W-LH, YX, H-YS, FY, L-LS and HW performed certain experiments, and were involved in related data analysis. L-LM, M-HL, W-WZ, S-LL and HL contributed to several experiments. MM, L-XD, B-SL, S-HS, Z-QZ, H-WC and JC provided patient samples and contributed to data interpretation. Z-HT and D-LH contributed to ideas and data interpretation.

Correspondence to Hong-Zhuan Chen or Cai-Wen Duan or Bin-Bing S. Zhou.

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