High STAT5A Expression is Associated with Major Molecular Response Achievement Failure of Chronic Phase Chronic Myeloid Leukemia Patients Receiving Hydroxyurea before Imatinib: A Cross-sectional Study

Ikhwan Rinaldi; Anastasia Putri; Melva Louisa; Sukamto Koesnoe

doi:10.3889/oamjms.2021.6911

Authors

Ikhwan Rinaldi Department of Internal Medicine, Division of Hematology and Medical Oncology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia https://orcid.org/0000-0002-6872-8802
Anastasia Putri Department of Internal Medicine, Division of Hematology and Medical Oncology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia
Melva Louisa Department of Pharmacology and Therapeutics, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia
Sukamto Koesnoe Department of Internal Medicine, Division of Allergy and Clinical Immunology, Faculty of Medicine, Universitas Indonesia, Cipto Mangunkusumo National General Hospital, Jakarta, Indonesia

DOI:

https://doi.org/10.3889/oamjms.2021.6911

Keywords:

Imatinib, Breakpoint cluster region-ABL, STAT5A, STAT5B, Chronic myeloid leukemia

Abstract

BACKGROUND: STAT5 is a transcriptional factor which when highly expressed in chronic myeloid leukemia (CML) cells stimulate proliferation and mediate resistance from tyrosine kinase inhibitors, resulting in major molecular response (MMR) failure. STAT5 has two isoforms, STAT5A and STAT5B. However, prolonged use of imatinib appears to only upregulate STAT5A pathway. In addition, the resistance conferred by STAT5A does not extend to other drugs such as hydroxyurea. Hence, STAT5A and STAT5B might have different functions in CML cells.

AIM: The objective of the study was to determine the association of STAT5A and STAT5B expression with MMR failure in CML patients.

METHODS: This was a cross-sectional study of CML patients in chronic phase with age ≥ 18 years old, receiving IM therapy ≥ 12 months, and previously given hydroxyurea. MMR status was evaluated and patients were categorized as achieved or failed to achieve MMR. Expression levels of STAT5A and STAT5B were conducted using RT-PCR methods. Associations between STAT5A expression, STAT5B expression, hydroxyurea duration, and imatinib duration with MMR achievement were calculated using logistic regression.

RESULTS: A total of 118 patients were analyzed; 71.1% failed to achieve MMR. Multivariate logistic regression analysis showed statistically significant association between high STAT5A expression (odds ratio [OR]: 3.852; 95% confidence interval [CI]: 1.420–10.452; p = 0.008), STAT5A/STAT5B interaction (OR: 0.150; 95% CI: 0.038–0.593; p = 0.007), longer hydroxyurea administration (OR: 3.882; 95% CI: 1.023–14.733; p = 0.046), and shorter imatinib administration (OR: 0.333; 95% CI: 0.132–0.840; p = 0.020) with MMR achievement failure. After adjusting STAT5A expression with STAT5A/STAT5B interaction, high STAT5A expression independently increased the likelihood of MMR achievement failure only in high expression STAT5B patients (OR: 3.852; 95% CI: 1.420–10.452; p = 0.008).

CONCLUSION: High STAT5A expression which is induced by high STAT5B is associated with MMR achievement failure of chronic phase CML patients who received hydroxyurea before imatinib. Longer duration of hydroxyurea and shorter duration of IM confound of STAT5A expression to MMR achievement failure.

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References

Granatowicz A, Piatek CI, Moschiano E, El-Hemaidi I, Armitage JD, Akhtari M. An overview and update of chronic myeloid leukemia for primary care physicians. Korean J Fam Med. 2015;36(5):197-202. http://doi.org/10.4082/kjfm.2015.36.5.197 PMid:26435808 DOI: https://doi.org/10.4082/kjfm.2015.36.5.197

Apperley JF. Chronic myeloid leukaemia. Lancet Lond Engl. 2015;385(9976):1447-59. http://doi.org/10.1016/S0140-6736(13)62120-0 PMid:25484026 DOI: https://doi.org/10.1016/S0140-6736(13)62120-0

Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol. 2018;93(3):442-59. http://doi.org/10.1002/ajh.25011 PMid:29411417 DOI: https://doi.org/10.1002/ajh.25011

Deininger MW, Vieira S, Mendiola R, Schultheis B, Goldman JM, Melo JV. BCR-ABL tyrosine kinase activity regulates the expression of multiple genes implicated in the pathogenesis of chronic myeloid leukemia. Cancer Res. 2000;60(7):2049-55. PMid:10766197

Casetti L. New Roles of STAT5 Factors in Chronic Myeloid Leukemia Cell Maintenance, No. 166; 2014.

Rinaldi I, Reksodiputro AH, Jusman SW, Harahap A, Setiabudy R, Wanandi SI, et al. Longer hydroxyurea administration prior to imatinib mesylate is risk factor for unsuccessful major molecular response in chronic-phase chronic myeloid leukemia: Possibility of p-glycoprotein role. Asian Pac J Cancer Prev. 2019;20(12):3689-95. https://doi.org/10.31557/APJCP.2019.20.12.3689 PMid:31870110 DOI: https://doi.org/10.31557/APJCP.2019.20.12.3689

Rizzieri D, Moore JO. Implementation of management guidelines for chronic myeloid leukemia. Pharm Ther. 2012;37(11):640-8. PMid:23204819

Wei G, Rafiyath S, Liu D. First-line treatment for chronic myeloid leukemia: Dasatinib, nilotinib, or imatinib. J Hematol Oncol. 2010;3:47. https://doi.org/10.1186/1756-8722-3-47 PMid:21108851 DOI: https://doi.org/10.1186/1756-8722-3-47

Valent P. Imatinib-resistant chronic myeloid leukemia (CML): Current concepts on pathogenesis and new emerging pharmacologic approaches. Biol Targets Ther. 2007;1(4):433-48. PMid:19707313

Legros L, Hayette S, Nicolini FE, Raynaud S, Chabane K, Magaud JP, et al. BCR-ABL T315I transcript disappearance in an imatinib-resistant CML patient treated with homoharringtonine: A new therapeutic challenge? Leukemia. 2007;21(10):2204-6. https://doi.org/10.1038/sj.leu.2404772 PMid:17541396 DOI: https://doi.org/10.1038/sj.leu.2404772

Warsch W, Kollmann K, Eckelhart E, Fajmann S, Cerny-Reiterer S, Hölbl A, et al. High STAT5 levels mediate imatinib resistance and indicate disease progression in chronic myeloid leukemia. Blood. 2011;117(12):3409-20. https://doi.org/10.1182/blood-2009-10-248211 PMid:21220747 DOI: https://doi.org/10.1182/blood-2009-10-248211

Dorritie KA, McCubrey JA, Johnson DE. STAT transcription factors in hematopoiesis and leukemogenesis: Opportunities for therapeutic intervention. Leukemia. 2014;28(2):248-57. https://doi.org/10.1038/leu.2013.192 PMid:23797472 DOI: https://doi.org/10.1038/leu.2013.192

Cheng Y, Hao Y, Zhang A, Hu C, Jiang X, Wu Q, et al. Persistent STAT5-mediated ROS production and involvement of aberrant p53 apoptotic signaling in the resistance of chronic myeloid leukemia to imatinib. Int J Mol Med. 2018;41(1):455-63. https://doi.org/10.3892/ijmm.2017.3205 PMid:29115375 DOI: https://doi.org/10.3892/ijmm.2017.3205

Zhang WW, Cortes JE, Yao H, Zhang L, Reddy NG, Jabbour E, et al. Predictors of primary imatinib resistance in chronic myelogenous leukemia are distinct from those in secondary imatinib resistance. J Clin Oncol. 2009;27(22):3642-49. https://doi.org/10.1200/JCO.2008.19.4076 PMid:19506164 DOI: https://doi.org/10.1200/JCO.2008.19.4076

Rousselot P, Roy L, Etienne G, Legros L, Charbonnier A, Coituex V, et al. Targeting STAT5 expression resulted in molecular response improvement in patients with chronic phase CML treated with imatinib. Blood. 2012;120(21):696-6. https://doi.org/10.1182/blood.V120.21.696.696 DOI: https://doi.org/10.1182/blood.V120.21.696.696

Tolomeo M, Meli M, Grimaudo S. STAT5 and STAT5 inhibitors in hematological malignancies. Anticancer Agents Med Chem. 2019;19(17):2036-46. http://doi.org/10.2174/187152061966619 0906160848 PMid:31490767 DOI: https://doi.org/10.2174/1871520619666190906160848

Gleixner KV, Schneeweiss M, Eisenwort G, Berger D, Herrmann H, Blatt K, et al. Combined targeting of STAT3 and STAT5: A novel approach to overcome drug resistance in chronic myeloid leukemia. Haematologica. 2017;102(9):1519-29. http://doi.org/10.3324/haematol.2016.163436 PMid:28596283 DOI: https://doi.org/10.3324/haematol.2016.163436

Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods San Diego Calif. 2001;25(4):402-8. http://doi.org/10.1006/meth.2001.1262 PMid:11846609 DOI: https://doi.org/10.1006/meth.2001.1262

Höglund M, Sandin F, Simonsson B. Epidemiology of chronic myeloid leukaemia: An update. Ann Hematol. 2015;94(Suppl 2):S241-7. http://doi.org/10.1007/s00277-015-2314-2 PMid:25814090 DOI: https://doi.org/10.1007/s00277-015-2314-2

Reksodiputro AH, Syafei S, Prayogo N, Karsono B, Rinaldi I, Rajabto W, et al. Clinical characteristics and hematologic responses to Imatinib in patients with chronic phase myeloid leukemia (CML) at Cipto Mangunkusumo Hospital. Acta Med Indones. 2010;42(1):2-5. PMid:20305324

Kantarjian H, Sawyers C, Hochhaus A, Guilhot F, Schiffer C, Gambacorti-Passerini C, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med. 2002;346(9):645-52. http://doi.org/10.1056/NEJMoa011573 PMid:11870241 DOI: https://doi.org/10.1056/NEJMoa011573

O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348(11):994-1004. http://doi.org/10.1056/NEJMoa022457 PMid:12637609 DOI: https://doi.org/10.1056/NEJMoa022457

Deininger M, O’Brien SG, Guilhot F, Goldman JM, Hochhause A, Hughes TP, et al. International randomized study of interferon Vs STI571 (IRIS) 8-year follow up: Sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) treated with imatinib. Blood. 2009;114(22):1126-6. DOI: https://doi.org/10.1182/blood.V114.22.1126.1126

Renault IZ, Scholl V, Hassan R, Capelleti P, de Lima M, Cortes J. The significance of major and stable molecular responses in chronic myeloid leukemia in the tyrosine kinase inhibitor era. Rev Bras Hematol. 2011;33(6):455-60. http://doi.org/10.5581/1516-8484.20110122 PMid:23049363 DOI: https://doi.org/10.5581/1516-8484.20110122

Sacha T. Imatinib in chronic myeloid leukemia: An overview. Mediterr J Hematol Infect Dis. 2014;6(1):e2014007. http://doi.org/10.4084/MJHID.2014.007 PMid:24455116 DOI: https://doi.org/10.4084/mjhid.2014.007

Melo JV, Chuah C. Resistance to imatinib mesylate in chronic myeloid leukaemia. Cancer Lett. 2007;249(2):121-32. http://doi.org/10.1016/j.canlet.2006.07.010 PMid:16949736 DOI: https://doi.org/10.1016/j.canlet.2006.07.010

Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, et al. Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy. Leukemia. 2002;16(11):2190-6. http://doi.org/10.1038/sj.leu.2402741 PMid:12399961 DOI: https://doi.org/10.1038/sj.leu.2402741

Kaymaz BT, Selvi N, Gündüz C, Aktan C, Dalmızrak A, Saydam G, et al. Repression of STAT3, STAT5A, and STAT5B expressions in chronic myelogenous leukemia cell line K-562 with unmodified or chemically modified siRNAs and induction of apoptosis. Ann Hematol. 2013;92(2):151-62. http://doi.org/10.1007/s00277-012-1575-2 PMid:23053176 DOI: https://doi.org/10.1007/s00277-012-1575-2

Schaller-Schönitz M, Barzan D, Williamson AJ, Griffiths JR, Dallmann I, Battmer K, et al. BCR-ABL Affects STAT5A and STAT5B Differentially. PLoS One. 2014;9(5):e97243. http://doi.org/10.1371/journal.pone.0097243 PMid:24836440 DOI: https://doi.org/10.1371/journal.pone.0097243

Mi T, Wang Z, Bunting KD. The cooperative relationship between STAT5 and reactive oxygen species in leukemia: Mechanism and therapeutic potential. Cancers. 2018;10(10):359. http://doi.org/10.3390/cancers10100359 PMid:30262727 DOI: https://doi.org/10.3390/cancers10100359

Casetti L, Martin-Lannerée S, Najjar I, Plo I, Augé S, Roy L, et al. Differential contributions of STAT5A and STAT5B to stress protection and tyrosine kinase inhibitor resistance of chronic myeloid leukemia stem/progenitor cells. Cancer Res. 2013;73(7):2052-8. http://doi.org/10.1158/0008-5472. CAN-12-3955 PMid:23400594 DOI: https://doi.org/10.1158/0008-5472.CAN-12-3955

Kollmann S, Grundschober E, Maurer B, Warsch W, Grausenburger R, Edlinger L, et al. Twins with different personalities: STAT5B but not STAT5A has a key role in BCR/ ABL-induced leukemia. Leukemia. 2019;33(7):1583-97. http://doi.org/10.1038/s41375-018-0369-5 PMid:30679796 DOI: https://doi.org/10.1038/s41375-018-0369-5