Acute myeloid leukemia

Elevated expression of S100A8 and S100A9 correlates with resistance to the BCL-2 inhibitor venetoclax in AML

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1
Fig. 2

References

  1. 1.

    DiNardo CD, Pratz K, Pullarkat V, Jonas BA, Arellano M, Becker PS, et al. Venetoclax combined with decitabine or azacitidine in treatment-naive, elderly patients with acute myeloid leukemia. Blood. 2019;133:7–17.

  2. 2.

    Tahir SK, Smith ML, Hessler P, Rapp LR, Idler KB, Park CH, et al. Potential mechanisms of resistance to venetoclax and strategies to circumvent it. BMC Cancer. 2017;17:399.

  3. 3.

    Lin KH, Winter PS, Xie A, Roth C, Martz CA, Stein EM, et al. Targeting MCL-1/BCL-XL forestalls the acquisition of resistance to ABT-199 in acute myeloid leukemia. Sci Rep. 2016;6:27696.

  4. 4.

    Chan SM, Thomas D, Corces-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, et al. Isocitrate dehydrogenase 1 and 2 mutations induce BCL-2 dependence in acute myeloid leukemia. Nat Med. 2015;21:178–84.

  5. 5.

    Kontro M, Kumar A, Majumder MM, Eldfors S, Parsons A, Pemovska T, et al. HOX gene expression predicts response to BCL-2 inhibition in acute myeloid leukemia. Leukemia. 2017;31:301–9.

  6. 6.

    Chyla B, Daver N, Doyle K, McKeegan E, Huang X, Ruvolo V, et al. Genetic biomarkers of sensitivity and resistance to venetoclax monotherapy in patients with relapsed acute myeloid leukemia. Am J Hematol. 2018. https://doi.org/10.1002/ajh.25146.

  7. 7.

    Ramsey HE, Fischer MA, Lee T, Gorska AE, Arrate MP, Fuller L, et al. A novel MCL1 inhibitor combined with venetoclax rescues venetoclax-resistant acute myelogenous leukemia. Cancer Discov. 2018;8:1566–81.

  8. 8.

    Karjalainen R, Pemovska T, Popa M, Liu M, Javarappa KK, Majumder MM, et al. JAK1/2 and BCL2 inhibitors synergize to counteract bone marrow stromal cell-induced protection of AML. Blood. 2017;130:789–802.

  9. 9.

    Bogenberger J, Whatcott C, Hansen N, Delman D, Shi CX, Kim W, et al. Combined venetoclax and alvocidib in acute myeloid leukemia. Oncotarget. 2017;8:107206–22.

  10. 10.

    Spijkers-Hagelstein JA, Schneider P, Hulleman E, de Boer J, Williams O, Pieters R, et al. Elevated S100A8/S100A9 expression causes glucocorticoid resistance in MLL-rearranged infant acute lymphoblastic leukemia. Leukemia. 2012;26:1255–65.

  11. 11.

    Simard JC, Cesaro A, Chapeton-Montes J, Tardif M, Antoine F, Girard D, et al. S100A8 and S100A9 induce cytokine expression and regulate the NLRP3 inflammasome via ROS-dependent activation of NF-kappaB(1.). PLoS ONE. 2013;8:e72138.

  12. 12.

    Jaiswal S, Natarajan P, Silver AJ, Gibson CJ, Bick AG, Shvartz E, et al. Clonal hematopoiesis and risk of atherosclerotic cardiovascular disease. N Engl J Med. 2017;377:111–21.

  13. 13.

    Cancer Genome Atlas Research N, Ley TJ, Miller C, Ding L, Raphael BJ, Mungall AJ, et al. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013;368:2059–74.

  14. 14.

    Fiskus W, Cai T, DiNardo CD, Kornblau SM, Borthakur G, Kadia TM, et al. Superior efficacy of cotreatment with BET protein inhibitor and BCL2 or MCL1 inhibitor against AML blast progenitor cells. Blood Cancer J. 2019;9:4.

  15. 15.

    Bui MH, Lin X, Albert DH, Li L, Lam LT, Faivre EJ, et al. Preclinical characterization of BET family bromodomain inhibitor ABBV-075 suggests combination therapeutic strategies. Cancer Res. 2017;77:2976–89.

Download references

Acknowledgements

We thank the patients and healthy donors for their samples and the research staff of the FIMM Technology Center, High Throughput Biomedicine Unit, the Breeze team, Hematology Research Unit, Minna Suvela and Siv Knaappila for their excellent technical assistance. We thank colleagues, Dr. Jarno Kivioja and  Dr. Heikki Kuusanmäki for their critical comments on the manuscript. The study was financially supported by the Finnish Funding Agency for Technology and Innovation - Tekes, the European Regional Development Funds, as well as grants from the Academy of Finland, Cancer Society of Finland and Sigrid Juselius Foundation. RK was supported by grants from the Cancer Society of Finland, K. Albin Johanssons stiftelse, Ida Montin Foundation, Orion Research Foundation, Oncology Society of Finland, and Väre Foundation for pediatric cancer research. AK received an EMBO short-term fellowship award and grants from the Cancer Society of Finland and Finnish Hematology Association. LH was supported by funding from the Integrated Life Sciences (ILS) doctoral program University of Helsinki, and a grant from the Cancer Society of Finland.

Author information

RK and ML designed the study, performed experiments, and analyzed the data; AK performed data analysis (collection, preprocessing, visualization, and machine learning). AP performed the RT-qPCR experiments and analysis. LH performed the drug combination synergy analysis. DM provided drug-sensitivity testing data in AML cell lines. MK and KP provided patient specimens and obtained institutional review board approval. CAH supervised the study. RK wrote the manuscript. ML, AK, and CAH participated in the writing and editing of the manuscript. All authors contributed to and approved the final version of the manuscript.

Correspondence to Caroline A. Heckman.

Ethics declarations

Conflict of interest

OK is a co-founder and a board member of Medisapiens and Sartar Therapeutics. He has received royalty on patents licensed from UC to Vysis-Abbot. His research group has a Vinnova-funded collaborative program with Astra-Zeneca, Labcyte, Takara Biosciences, and Pelago. KP has honoraria and grant support from Bristol-Myers Squibb, Celgene, Novartis, and Pfizer. CAH has received funding from Celgene, Orion Pharma, Novartis, Oncopeptides, and the Innovative Medicines Initiatives 2 project HARMONY. The other authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Supplementary Methods and Figures

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark