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Resistance to Targeted Therapies in Lymphomas pp 1–26Cite as

Mechanisms of Glucocorticoid Response and Resistance in Lymphoid Malignancies

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Part of the book series: Resistance to Targeted Anti-Cancer Therapeutics ((RTACT,volume 21))

Abstract

Glucocorticoids (GC) are an integral component of multi-agent therapy regimens for a wide variety of lymphoid malignancies due to their potential effects to induce apoptosis in cells of the lymphoid lineage. Despite their clinical utility, de novo and acquired resistance to GC is a significant clinical problem that contributes to inferior outcomes for many of these diseases. This review summarizes what is currently known about mechanisms of GC resistance in lymphoid malignancies, with a particular focus on novel therapeutic strategies currently in preclinical or clinical development that are rationally-designed to overcome GC resistance and improve clinical outcomes.

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Abbreviations

2-DG:

2-Deoxy-D-Glucose

3’UTR:

3’ Untranslated Region

B-CLL:

B-Cell Chronic Lymphocytic Leukemia

BFM:

Berlin-Frankfurt-Munster

cAMP:

Cyclic Adenosine Monophosphate

CDK:

Cyclin Dependent Kinase

ChIP-Seq:

Chromatin Immunoprecipitation with Sequencing

CHOP:

Cyclophosphamide, Adriamycin, Vincristine, and Prednisone

DBD:

DNA Binding Domain

DEX:

Dexamethasone

DLBCL:

Diffuse Large B-Cell Lymphoma

EFS:

Event-Free Survival

GC:

Glucocorticoid(s)

GR:

Glucocorticoid Receptor

GRE:

Glucocorticoid Response Element

GST:

Glutathione S-Transferase

HDAC:

Histone Deacetylase

HSD:

Hydroxysteroid Dehydrogenase

LBD:

Ligand Binding Domain

LOH:

Loss of Heterozygosity

MAPK:

Mitogen Activated Protein Kinase

miR:

MicroRNA

MRD:

Minimal Residual Disease

NCoR:

Nuclear Co-Receptor

NHL:

Non-Hodgkin Lymphoma

NTD:

N-Terminal Transactivation Domain

PDE:

Phosphodiesterase

PDX:

Patient-Derived Xenograft

PGR:

Prednisone Good Responder

PKA:

Protein Kinase A

PPR:

Prednisone Poor Responder

RT-PCR:

Real-Time Polymerase Chain Reaction

T-ALL:

T-Cell Acute Lymphoblastic Leukemia

TCR:

T-Cell Receptor

WBC:

White Blood Cell

References

  1. Schrappe M, Reiter A, Zimmermann M, Harbott J, Ludwig WD, Henze G, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Munster. Leukemia. 2000;14(12):2205–22.

    Article  CAS  PubMed  Google Scholar 

  2. Fisher RI, Gaynor ER, Dahlberg S, Oken MM, Grogan TM, Mize EM, et al. Comparison of a standard regimen (CHOP) with three intensive chemotherapy regimens for advanced non-Hodgkin’s lymphoma. N Engl J Med. 1993;328(14):1002–6.

    Article  CAS  PubMed  Google Scholar 

  3. Dordelmann M, Reiter A, Borkhardt A, Ludwig WD, Gotz N, Viehmann S, et al. Prednisone response is the strongest predictor of treatment outcome in infant acute lymphoblastic leukemia. Blood. 1999;94(4):1209–17.

    CAS  PubMed  Google Scholar 

  4. Mathew BS, Carson KA, Grossman SA. Initial response to glucocorticoids. Cancer. 2006;106(2):383–7.

    Article  PubMed  CAS  Google Scholar 

  5. Oakley RH, Cidlowski JA. The biology of the glucocorticoid receptor: new signaling mechanisms in health and disease. J Allergy Clin Immunol. 2013;132(5):1033–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamamoto KR. Steroid receptor regulated transcription of specific genes and gene networks. Annu Rev Genet. 1985;19:209–52.

    Article  CAS  PubMed  Google Scholar 

  7. Schmidt S, Rainer J, Ploner C, Presul E, Riml S, Kofler R. Glucocorticoid-induced apoptosis and glucocorticoid resistance: molecular mechanisms and clinical relevance. Cell Death Differ. 2004;11(Suppl 1):S45–55.

    Article  CAS  PubMed  Google Scholar 

  8. Ploner C, Rainer J, Niederegger H, Eduardoff M, Villunger A, Geley S, et al. The BCL2 rheostat in glucocorticoid-induced apoptosis of acute lymphoblastic leukemia. Leukemia. 2008;22(2):370–7.

    Article  CAS  PubMed  Google Scholar 

  9. 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(2):273–83.

    Article  CAS  PubMed  Google Scholar 

  10. Charmandari E, Kino T, Chrousos GP. Primary generalized familial and sporadic glucocorticoid resistance (Chrousos syndrome) and hypersensitivity. Endocr Dev. 2013;24:67–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Bray PJ, Cotton RG. Variations of the human glucocorticoid receptor gene (NR3C1): pathological and in vitro mutations and polymorphisms. Hum Mutat. 2003;21(6):557–68.

    Article  CAS  PubMed  Google Scholar 

  12. Harmon JM, Thompson EB. Isolation and characterization of dexamethasone-resistant mutants from human lymphoid cell line CEM-C7. Mol Cell Biol. 1981;1(6):512–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ashraf J, Thompson EB. Identification of the activation-labile gene: a single point mutation in the human glucocorticoid receptor presents as two distinct receptor phenotypes. Mol Endocrinol. 1993;7(5):631–42.

    CAS  PubMed  Google Scholar 

  14. Powers JH, Hillmann AG, Tang DC, Harmon JM. Cloning and expression of mutant glucocorticoid receptors from glucocorticoid-sensitive and -resistant human leukemic cells. Cancer Res. 1993;53(17):4059–65.

    CAS  PubMed  Google Scholar 

  15. Hala M, Hartmann BL, Bock G, Geley S, Kofler R. Glucocorticoid-receptor-gene defects and resistance to glucocorticoid-induced apoptosis in human leukemic cell lines. Int J Cancer. 1996;68(5):663–8.

    Article  CAS  PubMed  Google Scholar 

  16. Strasser-Wozak EM, Hattmannstorfer R, Hala M, Hartmann BL, Fiegl M, Geley S, et al. Splice site mutation in the glucocorticoid receptor gene causes resistance to glucocorticoid-induced apoptosis in a human acute leukemic cell line. Cancer Res. 1995;55(2):348–53.

    CAS  PubMed  Google Scholar 

  17. Hillmann AG, Ramdas J, Multanen K, Norman MR, Harmon JM. Glucocorticoid receptor gene mutations in leukemic cells acquired in vitro and in vivo. Cancer Res. 2000;60(7):2056–62.

    CAS  PubMed  Google Scholar 

  18. Riml S, Schmidt S, Ausserlechner MJ, Geley S, Kofler R. Glucocorticoid receptor heterozygosity combined with lack of receptor auto-induction causes glucocorticoid resistance in Jurkat acute lymphoblastic leukemia cells. Cell Death Differ. 2004;11(Suppl 1):S65–72.

    Article  CAS  PubMed  Google Scholar 

  19. Beesley AH, Weller RE, Senanayake S, Welch M, Kees UR. Receptor mutation is not a common mechanism of naturally occurring glucocorticoid resistance in leukaemia cell lines. Leuk Res. 2009;33(2):321–5.

    Article  CAS  PubMed  Google Scholar 

  20. Tissing WJ, Meijerink JP, den Boer ML, Brinkhof B, van Rossum EF, van Wering ER, et al. Genetic variations in the glucocorticoid receptor gene are not related to glucocorticoid resistance in childhood acute lymphoblastic leukemia. Clin Cancer Res. 2005;11(16):6050–6.

    Article  CAS  PubMed  Google Scholar 

  21. Irving JA, Minto L, Bailey S, Hall AG. Loss of heterozygosity and somatic mutations of the glucocorticoid receptor gene are rarely found at relapse in pediatric acute lymphoblastic leukemia but may occur in a subpopulation early in the disease course. Cancer Res. 2005;65(21):9712–8.

    Article  CAS  PubMed  Google Scholar 

  22. 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(5906):1377–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Oshima K, Khiabanian H, da Silva-Almeida AC, Tzoneva G, Abate F, Ambesi-Impiombato A, et al. Mutational landscape, clonal evolution patterns, and role of RAS mutations in relapsed acute lymphoblastic leukemia. Proc Natl Acad Sci USA. 2016;113(40):11306–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pui CH, Dahl GV, Rivera G, Murphy SB, Costlow ME. The relationship of blast cell glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia. Leuk Res. 1984;8(4):579–85.

    Article  CAS  PubMed  Google Scholar 

  25. Quddus FF, Leventhal BG, Boyett JM, Pullen DJ, Crist WM, Borowitz MJ. Glucocorticoid receptors in immunological subtypes of childhood acute lymphocytic leukemia cells: a pediatric oncology group study. Cancer Res. 1985;45(12 Pt 1):6482–6.

    CAS  PubMed  Google Scholar 

  26. Kato GJ, Quddus FF, Shuster JJ, Boyett J, Pullen JD, Borowitz MJ, et al. High glucocorticoid receptor content of leukemic blasts is a favorable prognostic factor in childhood acute lymphoblastic leukemia. Blood. 1993;82(8):2304–9.

    CAS  PubMed  Google Scholar 

  27. Grausenburger R, Bastelberger S, Eckert C, Kauer M, Stanulla M, Frech C, et al. Genetic alterations in glucocorticoid signaling pathway components are associated with adverse prognosis in children with relapsed ETV6/RUNX1-positive acute lymphoblastic leukemia. Leuk Lymphoma. 2016;57(5):1163–73.

    Article  CAS  PubMed  Google Scholar 

  28. Lauten M, Cario G, Asgedom G, Welte K, Schrappe M. Protein expression of the glucocorticoid receptor in childhood acute lymphoblastic leukemia. Haematologica. 2003;88(11):1253–8.

    CAS  PubMed  Google Scholar 

  29. Denton RR, Eisen LP, Elsasser MS, Harmon JM. Differential autoregulation of glucocorticoid receptor expression in human T- and B-cell lines. Endocrinology. 1993;133(1):248–56.

    Article  CAS  PubMed  Google Scholar 

  30. Ramdas J, Liu W, Harmon JM. Glucocorticoid-induced cell death requires autoinduction of glucocorticoid receptor expression in human leukemic T cells. Cancer Res. 1999;59(6):1378–85.

    CAS  PubMed  Google Scholar 

  31. Gomi M, Moriwaki K, Katagiri S, Kurata Y, Thompson EB. Glucocorticoid effects on myeloma cells in culture: correlation of growth inhibition with induction of glucocorticoid receptor messenger RNA. Cancer Res. 1990;50(6):1873–8.

    CAS  PubMed  Google Scholar 

  32. Asnafi V, Buzyn A, Le Noir S, Baleydier F, Simon A, Beldjord K, et al. NOTCH1/FBXW7 mutation identifies a large subgroup with favorable outcome in adult T-cell acute lymphoblastic leukemia (T-ALL): a Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) study. Blood. 2009;113(17):3918–24.

    Article  CAS  PubMed  Google Scholar 

  33. Clappier E, Collette S, Grardel N, Girard S, Suarez L, Brunie G, et al. NOTCH1 and FBXW7 mutations have a favorable impact on early response to treatment, but not on outcome, in children with T-cell acute lymphoblastic leukemia (T-ALL) treated on EORTC trials 58881 and 58951. Leukemia. 2010;24(12):2023–31.

    Article  CAS  PubMed  Google Scholar 

  34. Malyukova A, Brown S, Papa R, O’Brien R, Giles J, Trahair TN, et al. FBXW7 regulates glucocorticoid response in T-cell acute lymphoblastic leukaemia by targeting the glucocorticoid receptor for degradation. Leukemia. 2013;27(5):1053–62.

    Article  CAS  PubMed  Google Scholar 

  35. Paugh SW, Bonten EJ, Savic D, Ramsey LB, Thierfelder WE, Gurung P, et al. NALP3 inflammasome upregulation and CASP1 cleavage of the glucocorticoid receptor cause glucocorticoid resistance in leukemia cells. Nat Genet. 2015;47(6):607–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Oakley RH, Sar M, Cidlowski JA. The human glucocorticoid receptor beta isoform. Expression, biochemical properties, and putative function. J Biol Chem. 1996;271(16):9550–9.

    Article  CAS  PubMed  Google Scholar 

  37. Shahidi H, Vottero A, Stratakis CA, Taymans SE, Karl M, Longui CA, et al. Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia. Biochem Biophys Res Commun. 1999;254(3):559–65.

    Article  CAS  PubMed  Google Scholar 

  38. Koga Y, Matsuzaki A, Suminoe A, Hattori H, Kanemitsu S, Hara T. Differential mRNA expression of glucocorticoid receptor alpha and beta is associated with glucocorticoid sensitivity of acute lymphoblastic leukemia in children. Pediatr Blood Cancer. 2005;45(2):121–7.

    Article  PubMed  Google Scholar 

  39. Haarman EG, Kaspers GJ, Pieters R, Rottier MM, Veerman AJ. Glucocorticoid receptor alpha, beta and gamma expression vs in vitro glucocorticod resistance in childhood leukemia. Leukemia. 2004;18(3):530–7.

    Article  CAS  PubMed  Google Scholar 

  40. Beger C, Gerdes K, Lauten M, Tissing WJ, Fernandez-Munoz I, Schrappe M, et al. Expression and structural analysis of glucocorticoid receptor isoform gamma in human leukaemia cells using an isoform-specific real-time polymerase chain reaction approach. Br J Haematol. 2003;122(2):245–52.

    Article  CAS  PubMed  Google Scholar 

  41. Grad I, Picard D. The glucocorticoid responses are shaped by molecular chaperones. Mol Cell Endocrinol. 2007;275(1–2):2–12.

    Article  CAS  PubMed  Google Scholar 

  42. Lauten M, Beger C, Gerdes K, Asgedom G, Kardinal C, Welte K, et al. Expression of heat-shock protein 90 in glucocorticoid-sensitive and -resistant childhood acute lymphoblastic leukaemia. Leukemia. 2003;17(8):1551–6.

    Article  CAS  PubMed  Google Scholar 

  43. Tissing WJ, Meijerink JP, den Boer ML, Brinkhof B, Pieters R. mRNA expression levels of (co)chaperone molecules of the glucocorticoid receptor are not involved in glucocorticoid resistance in pediatric ALL. Leukemia. 2005;19(5):727–33.

    Article  CAS  PubMed  Google Scholar 

  44. John S, Sabo PJ, Johnson TA, Sung MH, Biddie SC, Lightman SL, et al. Interaction of the glucocorticoid receptor with the chromatin landscape. Mol Cell. 2008;29(5):611–24.

    Article  CAS  PubMed  Google Scholar 

  45. Pottier N, Yang W, Assem M, Panetta JC, Pei D, Paugh SW, et al. The SWI/SNF chromatin-remodeling complex and glucocorticoid resistance in acute lymphoblastic leukemia. J Natl Cancer Inst. 2008;100(24):1792–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Hogan LE, Meyer JA, Yang J, Wang J, Wong N, Yang W, et al. Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies. Blood. 2011;118(19):5218–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bhatla T, Wang J, Morrison DJ, Raetz EA, Burke MJ, Brown P, et al. Epigenetic reprogramming reverses the relapse-specific gene expression signature and restores chemosensitivity in childhood B-lymphoblastic leukemia. Blood. 2012;119(22):5201–10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Gruhn B, Naumann T, Gruner D, Walther M, Wittig S, Becker S, et al. The expression of histone deacetylase 4 is associated with prednisone poor-response in childhood acute lymphoblastic leukemia. Leuk Res. 2013;37(10):1200–7.

    Article  CAS  PubMed  Google Scholar 

  49. Jones CL, Bhatla T, Blum R, Wang J, Paugh SW, Wen X, et al. Loss of TBL1XR1 disrupts glucocorticoid receptor recruitment to chromatin and results in glucocorticoid resistance in a B-lymphoblastic leukemia model. J Biol Chem. 2014;289(30):20502–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Liu Y, Easton J, Shao Y, Maciaszek J, Wang Z, Wilkinson MR, et al. The genomic landscape of pediatric and young adult T-lineage acute lymphoblastic leukemia. Nat Genet. 2017;49(8):1211–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Zhang J, Mullighan CG, Harvey RC, Wu G, Chen X, Edmonson M, et al. Key pathways are frequently mutated in high-risk childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group. Blood. 2011;118(11):3080–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Moffitt AB, Dave SS. Clinical applications of the genomic landscape of aggressive non-hodgkin lymphoma. J Clin Oncol. 2017;35(9):955–62.

    Article  CAS  PubMed  Google Scholar 

  53. Revollo JR, Cidlowski JA. Mechanisms generating diversity in glucocorticoid receptor signaling. Ann NY Acad Sci. 2009;1179:167–78.

    Article  CAS  PubMed  Google Scholar 

  54. Raker VK, Becker C, Steinbrink K. The cAMP pathway as therapeutic target in autoimmune and inflammatory diseases. Front Immunol. 2016;7:123.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Gruol DJ, Campbell NF, Bourgeois S. Cyclic AMP-dependent protein kinase promotes glucocorticoid receptor function. J Biol Chem. 1986;261(11):4909–14.

    CAS  PubMed  Google Scholar 

  56. Medh RD, Saeed MF, Johnson BH, Thompson EB. Resistance of human leukemic CEM-C1 cells is overcome by synergism between glucocorticoid and protein kinase A pathways: correlation with c-Myc suppression. Cancer Res. 1998;58(16):3684–93.

    CAS  PubMed  Google Scholar 

  57. Zhang L, Insel PA. The pro-apoptotic protein Bim is a convergence point for cAMP/protein kinase A- and glucocorticoid-promoted apoptosis of lymphoid cells. J Biol Chem. 2004;279(20):20858–65.

    Article  CAS  PubMed  Google Scholar 

  58. Dong H, Carlton ME, Lerner A, Epstein PM. Effect of cAMP signaling on expression of glucocorticoid receptor, Bim and Bad in glucocorticoid-sensitive and resistant leukemic and multiple myeloma cells. Front Pharmacol. 2015;6:230.

    PubMed  PubMed Central  Google Scholar 

  59. Lerner A, Epstein PM. Cyclic nucleotide phosphodiesterases as targets for treatment of haematological malignancies. Biochem J. 2006;393(Pt 1):21–41.

    Article  CAS  PubMed  Google Scholar 

  60. Ogawa R, Streiff MB, Bugayenko A, Kato GJ. Inhibition of PDE4 phosphodiesterase activity induces growth suppression, apoptosis, glucocorticoid sensitivity, p53, and p21(WAF1/CIP1) proteins in human acute lymphoblastic leukemia cells. Blood. 2002;99(9):3390–7.

    Article  CAS  PubMed  Google Scholar 

  61. Tiwari S, Dong H, Kim EJ, Weintraub L, Epstein PM, Lerner A. Type 4 cAMP phosphodiesterase (PDE4) inhibitors augment glucocorticoid-mediated apoptosis in B cell chronic lymphocytic leukemia (B-CLL) in the absence of exogenous adenylyl cyclase stimulation. Biochem Pharmacol. 2005;69(3):473–83.

    Article  CAS  PubMed  Google Scholar 

  62. Meyers JA, Taverna J, Chaves J, Makkinje A, Lerner A. Phosphodiesterase 4 inhibitors augment levels of glucocorticoid receptor in B cell chronic lymphocytic leukemia but not in normal circulating hematopoietic cells. Clin Cancer Res. 2007;13(16):4920–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Kim SW, Rai D, Aguiar RC. Gene set enrichment analysis unveils the mechanism for the phosphodiesterase 4B control of glucocorticoid response in B-cell lymphoma. Clin Cancer Res. 2011;17(21):6723–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Shipp MA, Ross KN, Tamayo P, Weng AP, Kutok JL, Aguiar RC, et al. Diffuse large B-cell lymphoma outcome prediction by gene-expression profiling and supervised machine learning. Nat Med. 2002;8(1):68–74.

    Article  CAS  PubMed  Google Scholar 

  65. Pearson G, Robinson F, Beers Gibson T, Xu BE, Karandikar M, Berman K, et al. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22(2):153–83.

    CAS  PubMed  Google Scholar 

  66. Tanaka T, Okabe T, Gondo S, Fukuda M, Yamamoto M, Umemura T, et al. Modification of glucocorticoid sensitivity by MAP kinase signaling pathways in glucocorticoid-induced T-cell apoptosis. Exp Hematol. 2006;34(11):1542–52.

    Article  CAS  PubMed  Google Scholar 

  67. Miller AL, Webb MS, Copik AJ, Wang Y, Johnson BH, Kumar R, et al. p38 Mitogen-activated protein kinase (MAPK) is a key mediator in glucocorticoid-induced apoptosis of lymphoid cells: correlation between p38 MAPK activation and site-specific phosphorylation of the human glucocorticoid receptor at serine 211. Mol Endocrinol. 2005;19(6):1569–83.

    Article  CAS  PubMed  Google Scholar 

  68. 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(14):3539–44.

    Article  CAS  PubMed  Google Scholar 

  69. 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(43):15313–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Rambal AA, Panaguiton ZL, Kramer L, Grant S, Harada H. MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM. Leukemia. 2009;23(10):1744–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Rogatsky I, Logan SK, Garabedian MJ. Antagonism of glucocorticoid receptor transcriptional activation by the c-Jun N-terminal kinase. Proc Natl Acad Sci USA. 1998;95(5):2050–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. 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(19):2202–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Burotto M, Chiou VL, Lee JM, Kohn EC. The MAPK pathway across different malignancies: a new perspective. Cancer. 2014;120(22):3446–56.

    Article  CAS  PubMed  Google Scholar 

  74. Morishita N, Tsukahara H, Chayama K, Ishida T, Washio K, Miyamura T, et al. Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia. Pediatr Blood Cancer. 2012;59(1):83–9.

    Article  PubMed  Google Scholar 

  75. 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(6):766–76.

    Article  CAS  PubMed  Google Scholar 

  76. Kino T, Souvatzoglou E, De Martino MU, Tsopanomihalu M, Wan Y, Chrousos GP. Protein 14-3-3sigma interacts with and favors cytoplasmic subcellular localization of the glucocorticoid receptor, acting as a negative regulator of the glucocorticoid signaling pathway. J Biol Chem. 2003;278(28):25651–6.

    Article  CAS  PubMed  Google Scholar 

  77. Habib T, Sadoun A, Nader N, Suzuki S, Liu W, Jithesh PV, et al. AKT1 has dual actions on the glucocorticoid receptor by cooperating with 14-3-3. Mol Cell Endocrinol. 2017;439:431–43.

    Article  CAS  PubMed  Google Scholar 

  78. Silveira AB, Laranjeira AB, Rodrigues GO, Leal PC, Cardoso BA, Barata JT, et al. PI3K inhibition synergizes with glucocorticoids but antagonizes with methotrexate in T-cell acute lymphoblastic leukemia. Oncotarget. 2015;6(15):13105–18.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Evangelisti C, Cappellini A, Oliveira M, Fragoso R, Barata JT, Bertaina A, et al. Phosphatidylinositol 3-kinase inhibition potentiates glucocorticoid response in B-cell acute lymphoblastic leukemia. J Cell Physiol. 2018;233(3):1796–811.

    Article  CAS  PubMed  Google Scholar 

  80. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45.

    Article  CAS  PubMed  Google Scholar 

  81. Wei G, Twomey D, Lamb J, Schlis K, Agarwal J, Stam RW, et al. Gene expression-based chemical genomics identifies rapamycin as a modulator of MCL1 and glucocorticoid resistance. Cancer Cell. 2006;10(4):331–42.

    Article  CAS  PubMed  Google Scholar 

  82. Gu L, Zhou C, Liu H, Gao J, Li Q, Mu D, et al. Rapamycin sensitizes T-ALL cells to dexamethasone-induced apoptosis. J Exp Clin Cancer Res. 2010;29:150.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Batista A, Barata JT, Raderschall E, Sallan SE, Carlesso N, Nadler LM, et al. Targeting of active mTOR inhibits primary leukemia T cells and synergizes with cytotoxic drugs and signaling inhibitors. Exp Hematol. 2011;39(4):457–72.. e3

    Article  CAS  PubMed  Google Scholar 

  84. Zhang C, Ryu YK, Chen TZ, Hall CP, Webster DR, Kang MH. Synergistic activity of rapamycin and dexamethasone in vitro and in vivo in acute lymphoblastic leukemia via cell-cycle arrest and apoptosis. Leuk Res. 2012;36(3):342–9.

    Article  CAS  PubMed  Google Scholar 

  85. Schult C, Dahlhaus M, Glass A, Fischer K, Lange S, Freund M, et al. The dual kinase inhibitor NVP-BEZ235 in combination with cytotoxic drugs exerts anti-proliferative activity towards acute lymphoblastic leukemia cells. Anticancer Res. 2012;32(2):463–74.

    CAS  PubMed  Google Scholar 

  86. 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(3):621–32.

    Article  CAS  PubMed  Google Scholar 

  87. Murray PJ. The JAK-STAT signaling pathway: input and output integration. J Immunol. 2007;178(5):2623–9.

    Article  CAS  PubMed  Google Scholar 

  88. Roberts KG, Morin RD, Zhang J, Hirst M, Zhao Y, Su X, et al. Genetic alterations activating kinase and cytokine receptor signaling in high-risk acute lymphoblastic leukemia. Cancer Cell. 2012;22(2):153–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Stocklin E, Wissler M, Gouilleux F, Groner B. Functional interactions between Stat5 and the glucocorticoid receptor. Nature. 1996;383(6602):726–8.

    Article  CAS  PubMed  Google Scholar 

  90. Wu SC, Li LS, Kopp N, Montero J, Chapuy B, Yoda A, et al. Activity of the type II JAK2 inhibitor CHZ868 in B cell acute lymphoblastic leukemia. Cancer Cell. 2015;28(1):29–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. 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(12):2568–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Oppermann S, Lam AJ, Tung S, Shi Y, McCaw L, Wang G, et al. Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells. Oncotarget. 2016;7(45):72608–21.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Tzoneva G, Ferrando AA. Recent advances on NOTCH signaling in T-ALL. Curr Top Microbiol Immunol. 2012;360:163–82.

    CAS  PubMed  Google Scholar 

  94. De Keersmaecker K, Lahortiga I, Mentens N, Folens C, Van Neste L, Bekaert S, et al. In vitro validation of gamma-secretase inhibitors alone or in combination with other anti-cancer drugs for the treatment of T-cell acute lymphoblastic leukemia. Haematologica. 2008;93(4):533–42.

    Article  PubMed  CAS  Google Scholar 

  95. Real PJ, Tosello V, Palomero T, Castillo M, Hernando E, de Stanchina E, et al. Gamma-secretase inhibitors reverse glucocorticoid resistance in T cell acute lymphoblastic leukemia. Nat Med. 2009;15(1):50–8.

    Article  CAS  PubMed  Google Scholar 

  96. Samon JB, Castillo-Martin M, Hadler M, Ambesi-Impiobato A, Paietta E, Racevskis J, et al. Preclinical analysis of the gamma-secretase inhibitor PF-03084014 in combination with glucocorticoids in T-cell acute lymphoblastic leukemia. Mol Cancer Ther. 2012;11(7):1565–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Milano J, McKay J, Dagenais C, Foster-Brown L, Pognan F, Gadient R, et al. Modulation of notch processing by gamma-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci. 2004;82(1):341–58.

    Article  CAS  PubMed  Google Scholar 

  98. Agnusdei V, Minuzzo S, Frasson C, Grassi A, Axelrod F, Satyal S, et al. Therapeutic antibody targeting of Notch1 in T-acute lymphoblastic leukemia xenografts. Leukemia. 2014;28(2):278–88.

    Article  CAS  PubMed  Google Scholar 

  99. Palacios EH, Weiss A. Function of the Src-family kinases, Lck and Fyn, in T-cell development and activation. Oncogene. 2004;23(48):7990–8000.

    Article  CAS  PubMed  Google Scholar 

  100. Serafin V, Capuzzo G, Milani G, Minuzzo SA, Pinazza M, Bortolozzi R, et al. Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia. Blood. 2017;130(25):2750–61.

    Article  CAS  PubMed  Google Scholar 

  101. Harr MW, Caimi PF, McColl KS, Zhong F, Patel SN, Barr PM, et al. Inhibition of Lck enhances glucocorticoid sensitivity and apoptosis in lymphoid cell lines and in chronic lymphocytic leukemia. Cell Death Differ. 2010;17(9):1381–91.

    Article  CAS  PubMed  Google Scholar 

  102. Seckl JR. 11beta-hydroxysteroid dehydrogenases: changing glucocorticoid action. Curr Opin Pharmacol. 2004;4(6):597–602.

    Article  CAS  PubMed  Google Scholar 

  103. Sai S, Nakagawa Y, Sakaguchi K, Okada S, Takahashi H, Hongo T, et al. Differential regulation of 11beta-hydroxysteroid dehydrogenase-1 by dexamethasone in glucocorticoid-sensitive and -resistant childhood lymphoblastic leukemia. Leuk Res. 2009;33(12):1696–8.

    Article  CAS  PubMed  Google Scholar 

  104. Sai S, Nakagawa Y, Yamaguchi R, Suzuki M, Sakaguchi K, Okada S, et al. Expression of 11beta-hydroxysteroid dehydrogenase 2 contributes to glucocorticoid resistance in lymphoblastic leukemia cells. Leuk Res. 2011;35(12):1644–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Tao Y, Gao L, Wu X, Wang H, Yang G, Zhan F, et al. Down-regulation of 11beta-hydroxysteroid dehydrogenase type 2 by bortezomib sensitizes Jurkat leukemia T cells against glucocorticoid-induced apoptosis. PLoS One. 2013;8(6):e67067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Garbrecht MR, Schmidt TJ. Expression and regulation of 11- beta hydroxysteroid dehydrogenase type 2 enzyme activity in the glucocorticoid-sensitive CEM-C7 human leukemic cell line. ISRN Oncol. 2013;2013:245246.

    PubMed  PubMed Central  Google Scholar 

  107. Homma H, Maruyama H, Niitsu Y, Listowsky I. A subclass of glutathione S-transferases as intracellular high-capacity and high-affinity steroid-binding proteins. Biochem J. 1986;235(3):763–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Anderer G, Schrappe M, Brechlin AM, Lauten M, Muti P, Welte K, et al. Polymorphisms within glutathione S-transferase genes and initial response to glucocorticoids in childhood acute lymphoblastic leukaemia. Pharmacogenetics. 2000;10(8):715–26.

    Article  CAS  PubMed  Google Scholar 

  109. Beesley AH, Firth MJ, Ford J, Weller RE, Freitas JR, Perera KU, et al. Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism. Br J Cancer. 2009;100(12):1926–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Samuels AL, Heng JY, Beesley AH, Kees UR. Bioenergetic modulation overcomes glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia. Br J Haematol. 2014;165(1):57–66.

    Article  CAS  PubMed  Google Scholar 

  111. Holleman A, Cheok MH, den Boer ML, Yang W, Veerman AJ, Kazemier KM, et al. Gene-expression patterns in drug-resistant acute lymphoblastic leukemia cells and response to treatment. N Engl J Med. 2004;351(6):533–42.

    Article  CAS  PubMed  Google Scholar 

  112. Hulleman E, Kazemier KM, Holleman A, Vander Weele DJ, Rudin CM, Broekhuis MJ, et al. Inhibition of glycolysis modulates prednisolone resistance in acute lymphoblastic leukemia cells. Blood. 2009;113(9):2014–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Buentke E, Nordstrom A, Lin H, Bjorklund AC, Laane E, Harada M, et al. Glucocorticoid-induced cell death is mediated through reduced glucose metabolism in lymphoid leukemia cells. Blood Cancer J. 2011;1(7):e31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Aries IM, Hansen BR, Koch T, van den Dungen R, Evans WE, Pieters R, et al. The synergism of MCL1 and glycolysis on pediatric acute lymphoblastic leukemia cell survival and prednisolone resistance. Haematologica. 2013;98(12):1905–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pang YY, Wang T, Chen FY, Wu YL, Shao X, Xiao F, et al. Glycolytic inhibitor 2-deoxy-d-glucose suppresses cell proliferation and enhances methylprednisolone sensitivity in non-Hodgkin lymphoma cells through down-regulation of HIF-1alpha and c-MYC. Leuk Lymphoma. 2015;56(6):1821–30.

    Article  CAS  PubMed  Google Scholar 

  116. Chan LN, Chen Z, Braas D, Lee JW, Xiao G, Geng H, et al. Metabolic gatekeeper function of B-lymphoid transcription factors. Nature. 2017;542(7642):479–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Madden EA, Bishop EJ, Fiskin AM, Melnykovych G. Possible role of cholesterol in the susceptibility of a human acute lymphoblastic leukemia cell line to dexamethasone. Cancer Res. 1986;46(2):617–22.

    CAS  PubMed  Google Scholar 

  118. Samuels AL, Beesley AH, Yadav BD, Papa RA, Sutton R, Anderson D, et al. A pre-clinical model of resistance to induction therapy in pediatric acute lymphoblastic leukemia. Blood Cancer J. 2014;4:e232.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Lawrie CH. MicroRNAs in hematological malignancies. Blood Rev. 2013;27(3):143–54.

    Article  CAS  PubMed  Google Scholar 

  120. Han BW, Feng DD, Li ZG, Luo XQ, Zhang H, Li XJ, et al. A set of miRNAs that involve in the pathways of drug resistance and leukemic stem-cell differentiation is associated with the risk of relapse and glucocorticoid response in childhood ALL. Hum Mol Genet. 2011;20(24):4903–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Hezaveh K, Kloetgen A, Bernhart SH, Mahapatra KD, Lenze D, Richter J, et al. Alterations of microRNA and microRNA-regulated messenger RNA expression in germinal center B-cell lymphomas determined by integrative sequencing analysis. Haematologica. 2016;101(11):1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Harada M, Pokrovskaja-Tamm K, Soderhall S, Heyman M, Grander D, Corcoran M. Involvement of miR17 pathway in glucocorticoid-induced cell death in pediatric acute lymphoblastic leukemia. Leuk Lymphoma. 2012;53(10):2041–50.

    Article  CAS  PubMed  Google Scholar 

  123. Li XJ, Luo XQ, Han BW, Duan FT, Wei PP, Chen YQ. MicroRNA-100/99a, deregulated in acute lymphoblastic leukaemia, suppress proliferation and promote apoptosis by regulating the FKBP51 and IGF1R/mTOR signalling pathways. Br J Cancer. 2013;109(8):2189–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Ledderose C, Mohnle P, Limbeck E, Schutz S, Weis F, Rink J, et al. Corticosteroid resistance in sepsis is influenced by microRNA-124—induced downregulation of glucocorticoid receptor-alpha. Crit Care Med. 2012;40(10):2745–53.

    Article  CAS  PubMed  Google Scholar 

  125. Liang YN, Tang YL, Ke ZY, Chen YQ, Luo XQ, Zhang H, et al. MiR-124 contributes to glucocorticoid resistance in acute lymphoblastic leukemia by promoting proliferation, inhibiting apoptosis and targeting the glucocorticoid receptor. J Steroid Biochem Mol Biol. 2017;172:62–8.

    Article  CAS  PubMed  Google Scholar 

  126. Kim J, Jeong D, Nam J, Aung TN, Gim JA, Park KU, et al. MicroRNA-124 regulates glucocorticoid sensitivity by targeting phosphodiesterase 4B in diffuse large B cell lymphoma. Gene. 2015;558(1):173–80.

    Article  CAS  PubMed  Google Scholar 

  127. Kotani A, Ha D, Hsieh J, Rao PK, Schotte D, den Boer ML, et al. miR-128b is a potent glucocorticoid sensitizer in MLL-AF4 acute lymphocytic leukemia cells and exerts cooperative effects with miR-221. Blood. 2009;114(19):4169–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kotani A, Ha D, Schotte D, den Boer ML, Armstrong SA, Lodish HF. A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 acute lymphocytic leukemia cells. Cell Cycle. 2010;9(6):1037–42.

    Article  CAS  PubMed  Google Scholar 

  129. Huang B, Zhao J, Lei Z, Shen S, Li D, Shen GX, et al. miR-142-3p restricts cAMP production in CD4+CD25- T cells and CD4+CD25+ TREG cells by targeting AC9 mRNA. EMBO Rep. 2009;10(2):180–5.

    Article  CAS  PubMed  Google Scholar 

  130. Lv M, Zhang X, Jia H, Li D, Zhang B, Zhang H, et al. An oncogenic role of miR-142-3p in human T-cell acute lymphoblastic leukemia (T-ALL) by targeting glucocorticoid receptor-alpha and cAMP/PKA pathways. Leukemia. 2012;26(4):769–77.

    Article  CAS  PubMed  Google Scholar 

  131. Yang A, Ma J, Wu M, Qin W, Zhao B, Shi Y, et al. Aberrant microRNA-182 expression is associated with glucocorticoid resistance in lymphoblastic malignancies. Leuk Lymphoma. 2012;53(12):2465–73.

    Article  CAS  PubMed  Google Scholar 

  132. Chen P, Shen T, Wang H, Ke Z, Liang Y, Ouyang J, et al. MicroRNA-185-5p restores glucocorticoid sensitivity by suppressing the mammalian target of rapamycin complex (mTORC) signaling pathway to enhance glucocorticoid receptor autoregulation. Leuk Lymphoma. 2017:1–11.

    Google Scholar 

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Acknowledgements

L.K.M. is supported by the UCSF Medical Scientist Training Program Grant T32 GM007618 and by a Genentech Foundation Award. M.L.H is supported by the National Cancer Institute Grant R01 CA193776, The Campini Foundation, The Buster Posey Family Foundation, and The Pepp Family Foundation. The authors thank Kevin Shannon and Anica Wandler for their critical reading of the manuscript.

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No potential conflicts of interest were disclosed.

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Authors and Affiliations

  1. Department of Pediatrics, University of California, San Francisco, CA, USA

    Lauren K. Meyer & Michelle L. Hermiston

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  1. Lauren K. Meyer
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  2. Michelle L. Hermiston
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Correspondence to Michelle L. Hermiston .

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Editors and Affiliations

  1. Division of Hematology/Oncology, Department of Pediatrics, University of Alabama at Birmingham Children’s Hospital of Alabama, Birmingham, AL, USA

    Ana C. Xavier

  2. Departments of Pediatrics, Medicine, Pathology, Microbiology and Immunology, Cell Biology and Anatomy, New York Medical College, Valhalla, NY, USA

    Mitchell S. Cairo

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Meyer, L.K., Hermiston, M.L. (2019). Mechanisms of Glucocorticoid Response and Resistance in Lymphoid Malignancies. In: Xavier, A., Cairo, M. (eds) Resistance to Targeted Therapies in Lymphomas . Resistance to Targeted Anti-Cancer Therapeutics, vol 21. Springer, Cham. https://doi.org/10.1007/978-3-030-24424-8_1

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