Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Acute lymphoblastic leukemia

MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance

Leukemia volume 35, pages 3394–3405 (2021)Cite this article

Subjects

Abstract

(Patho-)physiological activation of the IL7-receptor (IL7R) signaling contributes to steroid resistance in pediatric T-cell acute lymphoblastic leukemia (T-ALL). Here, we show that activating IL7R pathway mutations and physiological IL7R signaling activate MAPK-ERK signaling, which provokes steroid resistance by phosphorylation of BIM. By mass spectrometry, we demonstrate that phosphorylated BIM is impaired in binding to BCL2, BCLXL and MCL1, shifting the apoptotic balance toward survival. Treatment with MEK inhibitors abolishes this inactivating phosphorylation of BIM and restores its interaction with anti-apoptotic BCL2-protein family members. Importantly, the MEK inhibitor selumetinib synergizes with steroids in both IL7-dependent and IL7-independent steroid resistant pediatric T-ALL PDX samples. Despite the anti-MAPK-ERK activity of ruxolitinib in IL7-induced signaling and JAK1 mutant cells, ruxolitinib only synergizes with steroid treatment in IL7-dependent steroid resistant PDX samples but not in IL7-independent steroid resistant PDX samples. Our study highlights the central role for MAPK-ERK signaling in steroid resistance in T-ALL patients, and demonstrates the broader application of MEK inhibitors over ruxolitinib to resensitize steroid-resistant T-ALL cells. These findings strongly support the enrollment of T-ALL patients in the current phase I/II SeluDex trial (NCT03705507) and contributes to the optimization and stratification of newly designed T-ALL treatment regimens.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: IL7R signaling mutations and physiological IL7-signaling activates MAPK-ERK signaling in T-ALL.
Fig. 2: Pro-apoptotic BIM is phosphorylated downstream of activated MAPK-ERK signaling.
Fig. 3: Steroid-dependent expression of BIM is not impaired in MAPK-ERK activated cell lines.
Fig. 4: Phosphorylation of BIM directly impairs its binding to anti-apoptotic proteins, which is prevented by pharmacological inhibition of MAPK-ERK signaling.
Fig. 5: MEK-inhibitors synergize with steroid treatment in IL7-dependent and IL7-independent steroid-resistant T-ALL.
Fig. 6: Schematic overview of MAPK-ERK-induced steroid resistance.

Similar content being viewed by others

References

  1. Pieters R, de Groot-Kruseman H, Van der Velden V, Fiocco M, van den Berg H, de Bont E, et al. Successful Therapy Reduction and Intensification for Childhood Acute Lymphoblastic Leukemia Based on Minimal Residual Disease Monitoring: study ALL10 From the Dutch Childhood Oncology Group. J Clin Oncol. 2016;34:2591–601.

    Article  PubMed  Google Scholar 

  2. Conter V, Valsecchi MG, Parasole R, Putti MC, Locatelli F, Barisone E, et al. Childhood high-risk acute lymphoblastic leukemia in first remission: results after chemotherapy or transplant from the AIEOP ALL 2000 study. Blood. 2014;123:1470–8.

    Article  CAS  PubMed  Google Scholar 

  3. Lauten M, Moricke A, Beier R, Zimmermann M, Stanulla M, Meissner B, et al. Prediction of outcome by early bone marrow response in childhood acute lymphoblastic leukemia treated in the ALL-BFM 95 trial: differential effects in precursor B-cell and T-cell leukemia. Haematologica. 2012;97:1048–56.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Reedijk AMJ, Coebergh JWW, de Groot-Kruseman HA, van der Sluis IM, Kremer LC, Karim-Kos HE, et al. Progress against childhood and adolescent acute lymphoblastic leukaemia in the Netherlands, 1990-2015. Leukemia. 2021;35:1001–11.

    Article  PubMed  Google Scholar 

  5. Kaspers GJ, Pieters R, Van Zantwijk CH, Van Wering ER, Van Der Does-Van Den Berg A, Veerman AJ. Prednisolone resistance in childhood acute lymphoblastic leukemia: vitro-vivo correlations and cross-resistance to other drugs. Blood. 1998;92:259–66.

    Article  CAS  PubMed  Google Scholar 

  6. Lauten M, Stanulla M, Zimmermann M, Welte K, Riehm H, Schrappe M. Clinical outcome of patients with childhood acute lymphoblastic leukaemia and an initial leukaemic blood blast count of less than 1000 per microliter. Klinische Padiatrie. 2001;213:169–74.

    Article  CAS  PubMed  Google Scholar 

  7. O’Connor L, Strasser A, O’Reilly LA, Hausmann G, Adams JM, Cory S, et al. Bim: a novel member of the Bcl-2 family that promotes apoptosis. EMBO J. 1998;17:384–95.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Jing D, Bhadri VA, Beck D, Thoms JA, Yakob NA, Wong JW, et al. Opposing regulation of BIM and BCL2 controls glucocorticoid-induced apoptosis of pediatric acute lymphoblastic leukemia cells. Blood. 2015;125:273–83.

    Article  CAS  PubMed  Google Scholar 

  9. Abrams MT, Robertson NM, Yoon K, Wickstrom E. Inhibition of glucocorticoid-induced apoptosis by targeting the major splice variants of BIM mRNA with small interfering RNA and short hairpin RNA. J Biol Chem. 2004;279:55809–17.

    Article  CAS  PubMed  Google Scholar 

  10. Hall CP, Reynolds CP, Kang MH. Modulation of Glucocorticoid Resistance in Pediatric T-cell Acute Lymphoblastic Leukemia by Increasing BIM Expression with the PI3K/mTOR Inhibitor BEZ235. Clin Cancer Res. 2016;22:621–32.

    Article  CAS  PubMed  Google Scholar 

  11. Ley R, Balmanno K, Hadfield K, Weston C, Cook SJ. Activation of the ERK1/2 signaling pathway promotes phosphorylation and proteasome-dependent degradation of the BH3-only protein, Bim. J Biol Chem. 2003;278:18811–6.

    Article  CAS  PubMed  Google Scholar 

  12. Wang Z, Malone MH, He H, McColl KS, Distelhorst CW. Microarray analysis uncovers the induction of the proapoptotic BH3-only protein Bim in multiple models of glucocorticoid-induced apoptosis. J Biol Chem. 2003;278:23861–7.

    Article  CAS  PubMed  Google Scholar 

  13. Wang C, Youle RJ. The role of mitochondria in apoptosis*. Annu Rev Genet. 2009;43:95–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Willis SN, Fletcher JI, Kaufmann T, van Delft MF, Chen L, Czabotar PE, et al. Apoptosis initiated when BH3 ligands engage multiple Bcl-2 homologs, not Bax or Bak. Science. 2007;315:856–9.

    Article  CAS  PubMed  Google Scholar 

  15. Gavathiotis E, Suzuki M, Davis ML, Pitter K, Bird GH, Katz SG, et al. BAX activation is initiated at a novel interaction site. Nature. 2008;455:1076–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Piovan E, Yu J, Tosello V, Herranz D, Ambesi-Impiombato A, Da Silva AC, et al. Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia. Cancer Cell. 2013;24:766–76.

    Article  CAS  PubMed  Google Scholar 

  17. Bachmann PS, Gorman R, Papa RA, Bardell JE, Ford J, Kees UR, et al. Divergent mechanisms of glucocorticoid resistance in experimental models of pediatric acute lymphoblastic leukemia. Cancer Res. 2007;67:4482–90.

    Article  CAS  PubMed  Google Scholar 

  18. Bachmann PS, Piazza RG, Janes ME, Wong NC, Davies C, Mogavero A, et al. Epigenetic silencing of BIM in glucocorticoid poor-responsive pediatric acute lymphoblastic leukemia, and its reversal by histone deacetylase inhibition. Blood. 2010;116:3013–22.

    Article  CAS  PubMed  Google Scholar 

  19. Singh A, Ye M, Bucur O, Zhu S, Tanya Santos M, Rabinovitz I, et al. Protein phosphatase 2A reactivates FOXO3a through a dynamic interplay with 14-3-3 and AKT. Mol Biol Cell. 2010;21:1140–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang JY, Zong CS, Xia W, Yamaguchi H, Ding Q, Xie X, et al. ERK promotes tumorigenesis by inhibiting FOXO3a via MDM2-mediated degradation. Nat Cell Biol. 2008;10:138–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Lu J, Quearry B, Harada H. p38-MAP kinase activation followed by BIM induction is essential for glucocorticoid-induced apoptosis in lymphoblastic leukemia cells. FEBS Lett. 2006;580:3539–44.

    Article  CAS  PubMed  Google Scholar 

  22. Hubner A, Barrett T, Flavell RA, Davis RJ. Multisite phosphorylation regulates Bim stability and apoptotic activity. Mol Cell. 2008;30:415–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Leung KT, Li KK, Sun SS, Chan PK, Ooi VE, Chiu LC. Activation of the JNK pathway promotes phosphorylation and degradation of BimEL-a novel mechanism of chemoresistance in T-cell acute lymphoblastic leukemia. Carcinogenesis. 2008;29:544–51.

    Article  CAS  PubMed  Google Scholar 

  24. Lei K, Davis RJ. JNK phosphorylation of Bim-related members of the Bcl2 family induces Bax-dependent apoptosis. Proc Natl Acad Sci USA. 2003;100:2432–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Barata JT, Silva A, Brandao JG, Nadler LM, Cardoso AA, Boussiotis VA. Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med. 2004;200:659–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ribeiro D, Melao A, van Boxtel R, Santos CI, Silva A, Silva MC, et al. STAT5 is essential for IL-7-mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells. Blood Adv. 2018;2:2199–213.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Silva A, Laranjeira AB, Martins LR, Cardoso BA, Demengeot J, Yunes JA, et al. IL-7 contributes to the progression of human T-cell acute lymphoblastic leukemias. Cancer Res. 2011;71:4780–9.

    Article  CAS  PubMed  Google Scholar 

  28. Li Y, Buijs-Gladdines JG, Cante-Barrett K, Stubbs AP, Vroegindeweij EM, Smits WK, et al. IL-7 Receptor Mutations and Steroid Resistance in Pediatric T cell Acute Lymphoblastic Leukemia: a Genome Sequencing Study. PLoS Med. 2016;13:e1002200.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Delgado-Martin C, Meyer LK, Huang BJ, Shimano KA, Zinter MS, Nguyen JV, et al. JAK/STAT pathway inhibition overcomes IL7-induced glucocorticoid resistance in a subset of human T-cell acute lymphoblastic leukemias. Leukemia. 2017;31:2568–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Meyer LK, Huang BJ, Delgado-Martin C, Roy RP, Hechmer A, Wandler AM, et al. Glucocorticoids paradoxically facilitate steroid resistance in T-cell acute lymphoblastic leukemias and thymocytes. J Clin Investig. 2020;130:863–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Barata JT, Durum SK, Seddon B. Flip the coin: IL-7 and IL-7R in health and disease. Nat Immunol. 2019;20:1584–93.

    Article  CAS  PubMed  Google Scholar 

  32. Erlacher M, Michalak EM, Kelly PN, Labi V, Niederegger H, Coultas L, et al. BH3-only proteins Puma and Bim are rate-limiting for gamma-radiation- and glucocorticoid-induced apoptosis of lymphoid cells in vivo. Blood. 2005;106:4131–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Jing D, Huang Y, Liu X, Sia KCS, Zhang JC, Tai X, et al. Lymphocyte-Specific Chromatin Accessibility Pre-determines Glucocorticoid Resistance in Acute Lymphoblastic Leukemia. Cancer Cell. 2018;34:906–21. e8.

    Article  CAS  PubMed  Google Scholar 

  34. Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, et al. BCL-2, BCL-X(L) sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell. 2001;8:705–11.

    Article  CAS  PubMed  Google Scholar 

  35. Puthalakath H, Huang DC, O’Reilly LA, King SM, Strasser A. The proapoptotic activity of the Bcl-2 family member Bim is regulated by interaction with the dynein motor complex. Mol Cell. 1999;3:287–96.

    Article  CAS  PubMed  Google Scholar 

  36. Gomez-Bougie P, Bataille R, Amiot M. Endogenous association of Bim BH3-only protein with Mcl-1, Bcl-xL and Bcl-2 on mitochondria in human B cells. Eur J Immunol. 2005;35:971–6.

    Article  CAS  PubMed  Google Scholar 

  37. Korfi K, Smith M, Swan J, Somervaille TC, Dhomen N, Marais R. BIM mediates synergistic killing of B-cell acute lymphoblastic leukemia cells by BCL-2 and MEK inhibitors. Cell Death Dis. 2016;7:e2177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Maude SL, Dolai S, Delgado-Martin C, Vincent T, Robbins A, Selvanathan A, et al. Efficacy of JAK/STAT pathway inhibition in murine xenograft models of early T-cell precursor (ETP) acute lymphoblastic leukemia. Blood. 2015;125:1759–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Gianfelici V, Chiaretti S, Demeyer S, Di Giacomo F, Messina M, La Starza R, et al. RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications. Haematologica. 2016;101:941–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Trinquand A, Tanguy-Schmidt A, Ben Abdelali R, Lambert J, Beldjord K, Lengline E, et al. Toward a NOTCH1/FBXW7/RAS/PTEN-based oncogenetic risk classification of adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study. J Clin Oncol. 2013;31:4333–42.

    Article  CAS  PubMed  Google Scholar 

  41. Richter-Pechanska P, Kunz JB, Hof J, Zimmermann M, Rausch T, Bandapalli OR, et al. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. Blood Cancer J. 2017;7:e523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Harada H, Quearry B, Ruiz-Vela A, Korsmeyer SJ. Survival factor-induced extracellular signal-regulated kinase phosphorylates BIM, inhibiting its association with BAX and proapoptotic activity. Proc Natl Acad Sci USA. 2004;101:15313–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Biswas SC, Greene LA. Nerve growth factor (NGF) down-regulates the Bcl-2 homology 3 (BH3) domain-only protein Bim and suppresses its proapoptotic activity by phosphorylation. J Biol Chem. 2002;277:49511–6.

    Article  CAS  PubMed  Google Scholar 

  44. Moustafa-Kamal M, Gamache I, Lu Y, Li S, Teodoro JG. BimEL is phosphorylated at mitosis by Aurora A and targeted for degradation by betaTrCP1. Cell Death Differ. 2013;20:1393–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Gilley R, Lochhead PA, Balmanno K, Oxley D, Clark J, Cook SJ. CDK1, not ERK1/2 or ERK5, is required for mitotic phosphorylation of BIMEL. Cell Signal. 2012;24:170–80.

    Article  CAS  PubMed  Google Scholar 

  46. Bhadri VA, Cowley MJ, Kaplan W, Trahair TN, Lock RB. Evaluation of the NOD/SCID xenograft model for glucocorticoid-regulated gene expression in childhood B-cell precursor acute lymphoblastic leukemia. BMC Genom. 2011;12:565.

    Article  CAS  Google Scholar 

  47. Verbeke D, Gielen O, Jacobs K, Boeckx N, De Keersmaecker K, Maertens J, et al. Ruxolitinib Synergizes With Dexamethasone for the Treatment of T-cell Acute Lymphoblastic Leukemia. Hemasphere. 2019;3:e310.

    Article  PubMed  PubMed Central  Google Scholar 

  48. Greenfield G, McPherson S, Mills K, McMullin MF. The ruxolitinib effect: understanding how molecular pathogenesis and epigenetic dysregulation impact therapeutic efficacy in myeloproliferative neoplasms. J Transl Med. 2018;16:360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Irving J, Matheson E, Minto L, Blair H, Case M, Halsey C, et al. Ras pathway mutations are prevalent in relapsed childhood acute lymphoblastic leukemia and confer sensitivity to MEK inhibition. Blood. 2014;124:3420–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Matheson EC, Thomas H, Case M, Blair H, Jackson RK, Masic D, et al. Glucocorticoids and selumetinib are highly synergistic in RAS pathway mutated childhood acute lymphoblastic leukemia through upregulation of BIM. Haematologica. 2019;104:1804–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Jones CL, Gearheart CM, Fosmire S, Delgado-Martin C, Evensen NA, Bride K, et al. MAPK signaling cascades mediate distinct glucocorticoid resistance mechanisms in pediatric leukemia. Blood. 2015;126:2202–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

This study was sponsored by grants of the foundation “Kinderen Kankervrij”; KiKa-219 (JvdZ), KiKa-92, KiKa-295 (WKS), the Chemotherapy Foundation (AAF) and NIH grants P30 CA013696 (Flow Cytometry Shared Resource and Genomics Shared Resource, Herbert Irving Comprehensive Cancer Center) and R35 CA210065 (AAF). This research was part of the Netherlands X-omics Initiative and partially funded by NWO, project 184.034.019.

Funding

JV and BV: Cancer Research United Kingdom alliance funding from AstraZeneca for SeluDex trial (NCT03705507).

Author information

Authors and Affiliations

  1. Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands

    Jordy C. G. van der Zwet, Jessica G. C. A. M. Buijs-Gladdines, Valentina Cordo’, Willem K. Smits, Zhongli Chen, Josef Vormoor, Rob Pieters, Britta Vormoor & Jules P. P. Meijerink

  2. Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center of Biomolecular Research and Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, the Netherlands

    Donna O. Debets & Maarten Altelaar

  3. Netherlands Translational Research Center B.V., Oss, the Netherlands

    Jelle Dylus & Guido J. R. Zaman

  4. Institute of Cancer Genetics, Columbia University Medical Center, New York, NY, USA

    Koichi Oshima & Adolfo A. Ferrando

  5. Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland

    Beat Bornhauser & Jean-Pierre Bourquin

  6. KU Leuven Center for Human Genetics & VIB Center for Cancer Biology, Leuven, Belgium

    Jan Cools

  7. Newcastle University, Newcastle upon Tyne, UK

    Josef Vormoor

Authors
  1. Jordy C. G. van der Zwet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica G. C. A. M. Buijs-Gladdines
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Valentina Cordo’
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Donna O. Debets
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Willem K. Smits
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Zhongli Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Jelle Dylus
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Guido J. R. Zaman
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maarten Altelaar
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Koichi Oshima
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Beat Bornhauser
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Jean-Pierre Bourquin
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Jan Cools
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Adolfo A. Ferrando
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Josef Vormoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Rob Pieters
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Britta Vormoor
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Jules P. P. Meijerink
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JvdZ designed study, performed research and wrote paper. JBG, VC, DD, WKS, ZC and JD performed research. GZ, MA, KO, BB, J-PB, JC and AAF performed research, and provided critical input. JV, RP and BV provided critical input and wrote paper. JM designed and supervised the study and wrote paper.

Corresponding author

Correspondence to Jules P. P. Meijerink.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

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

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

van der Zwet, J.C.G., Buijs-Gladdines, J.G.C.A.M., Cordo’, V. et al. MAPK-ERK is a central pathway in T-cell acute lymphoblastic leukemia that drives steroid resistance. Leukemia 35, 3394–3405 (2021). https://doi.org/10.1038/s41375-021-01291-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41375-021-01291-5

This article is cited by

Search

Advanced search

Quick links