HSH2D contributes to methotrexate resistance in human T‑cell acute lymphoblastic leukaemia

Wang,Jing; Xiong,Yiying

doi:10.3892/or.2020.7772

HSH2D contributes to methotrexate resistance in human T‑cell acute lymphoblastic leukaemia

Authors:
- Jing Wang
- Yiying Xiong
View Affiliations

Affiliations: Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
Published online on: September 17, 2020 https://doi.org/10.3892/or.2020.7772
Pages: 2121-2129
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Acute lymphoblastic leukaemia (ALL) is a malignant proliferative disease that originates from B‑lineage or T‑lineage lymphoid progenitor cells. Resistance to chemotherapy remains an important factor for treatment failure. The aim of the present study was to investigate drug resistance in T‑cell ALL (T‑ALL). Bioinformatics analysis of Oncomine and Gene Expression Omnibus data was performed to evaluate the expression of haematopoietic SH2 domain containing (HSH2D) in various lymphomas. HuT‑78 cells with HSH2D overexpression and or knockdown were constructed, and the effect on related downstream signalling molecules was detected. To study the effect of HSH2D on methotrexate (MTX) resistance, cell cycle and apoptosis analyses were conducted using flow cytometry, and MTT and EdU assays were used to detect the effect of MTX resistance and HSH2D gene expression on the biological function of HuT‑78 cells. Via the analysis of the data sets, it was identified that the expression of HSH2D was downregulated in T‑ALL compared with B‑cell ALL. Western blotting and reverse transcription‑quantitative PCR demonstrated that the overexpression of HSH2 resulted in the inhibition of CD28‑mediated IL‑2 activation. In related experiments with drug‑resistant cell lines, it was determined that HSH2D expression is necessary for HuT‑78 cells to be resistant to MTX. In conclusion, the results suggested that HSH2D serves an important role in the resistance of T‑ALL to MTX, which provides a potential research target for the study of drug resistance of T‑ALL.

View Figures

View References

1	Singh N, Frey NV, Grupp SA and Maude SL: CAR T cell therapy in acute lymphoblastic leukemia and potential for chronic lymphocytic leukemia. Curr Treat Options Oncol. 17:282016. View Article : Google Scholar : PubMed/NCBI
2	Swaminathan S, Klemm L, Park E, Papaemmanuil E, Ford A, Kweon SM, Trageser D, Hasselfeld B, Henke N, Mooster J, et al: Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol. 16:766–774. 2015. View Article : Google Scholar : PubMed/NCBI
3	Belver L and Ferrando A: The genetics and mechanisms of T cell acute lymphoblastic leukaemia. Nat Rev Cancer. 16:494–507. 2016. View Article : Google Scholar : PubMed/NCBI
4	Roberts KG and Mullighan CG: Genomics in acute lymphoblastic leukaemia: Insights and treatment implications. Nat Rev Clin Oncol. 12:344–357. 2015. View Article : Google Scholar : PubMed/NCBI
5	Conter V, Valsecchi MG, Buldini B, Parasole R, Locatelli F, Colombini A, Rizzari C, Putti MC, Barisone E, Lo Nigro L, et al: Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: A retrospective analysis. Lancet Haematol. 3:e80–e86. 2016. View Article : Google Scholar : PubMed/NCBI
6	Cooper SL and Brown PA: Treatment of pediatric acute lymphoblastic leukemia. Pediatr Clin North Am. 62:61–73. 2015. View Article : Google Scholar : PubMed/NCBI
7	Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, Wei A, Dombret H, Foà R, Bassan R, et al: Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 376:836–847. 2017. View Article : Google Scholar : PubMed/NCBI
8	Pui CH, Yang JJ, Hunger SP, Pieters R, Schrappe M, Biondi A, Vora A, Baruchel A, Silverman LB, Schmiegelow K, et al: Childhood acute lymphoblastic leukemia: Progress through collaboration. J Clin Oncol. 33:2938–2948. 2015. View Article : Google Scholar : PubMed/NCBI
9	Grohmann T, Penke M, Petzold-Quinque S, Schuster S, Richter S, Kiess W and Garten A: Inhibition of NAMPT sensitizes MOLT4 leukemia cells for etoposide treatment through the SIRT2-p53 pathway. Leuk Res. 69:39–46. 2018. View Article : Google Scholar : PubMed/NCBI
10	Bartram I, Erben U, Ortiz-Tanchez J, Blunert K, Schlee C, Neumann M, Heesch S and Baldus CD: Inhibition of IGF1-R overcomes IGFBP7-induced chemotherapy resistance in T-ALL. BMC Cancer. 15:6632015. View Article : Google Scholar : PubMed/NCBI
11	Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, et al: Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 7:303ra1392015. View Article : Google Scholar : PubMed/NCBI
12	Jain N, Lamb AV, O'Brien S, Ravandi F, Konopleva M, Jabbour E, Zuo Z, Jorgensen J, Lin P, Pierce S, et al: Early T-cell precursor acute lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) in adolescents and adults: A high-risk subtype. Blood. 127:1863–1869. 2016. View Article : Google Scholar : PubMed/NCBI
13	Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, Easton J, Chen X, Wang J, Rusch M, et al: The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Nature. 481:157–163. 2012. View Article : Google Scholar : PubMed/NCBI
14	Neumann M, Heesch S, Schlee C, Schwartz S, Gökbuget N, Hoelzer D, Konstandin NP, Ksienzyk B, Vosberg S, Graf A, et al: Whole-exome sequencing in adult ETP-ALL reveals a high rate of DNMT3A mutations. Blood. 121:4749–4752. 2013. View Article : Google Scholar : PubMed/NCBI
15	Oda T, Muramatsu MA, Isogai T, Masuho Y, Asano S and Yamashita T: HSH2: A novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells. Biochem Biophys Res Commun. 288:1078–1086. 2001. View Article : Google Scholar : PubMed/NCBI
16	Lapinski PE, Oliver JA, Bodie JN, Marti F and King PD: The T-cell-specific adapter protein family: TSAd, ALX, and SH2D4A/SH2D4B. Immunol Rev. 232:240–254. 2009. View Article : Google Scholar : PubMed/NCBI
17	Pegram HJ, Purdon TJ, van Leeuwen DG, Curran KJ, Giralt SA, Barker JN and Brentjens RJ: IL-12-secreting CD19-targeted cord blood-derived T cells for the immunotherapy of B-cell acute lymphoblastic leukemia. Leukemia. 29:415–422. 2015. View Article : Google Scholar : PubMed/NCBI
18	Shapiro MJ, Powell P, Ndubuizu A, Nzerem C and Shapiro VS: The ALX Src homology 2 domain is both necessary and sufficient to inhibit T cell receptor/CD28-mediated up-regulation of RE/AP. J Biol Chem. 279:40647–40652. 2004. View Article : Google Scholar : PubMed/NCBI
19	Haferlach T, Kohlmann A, Wieczorek L, Basso G, Kronnie GT, Béné MC, De Vos J, Hernández JM, Hofmann WK, Mills KI, et al: Clinical utility of microarray-based gene expression profiling in the diagnosis and subclassification of leukemia: Report from the International microarray innovations in leukemia study group. J Clin Oncol. 28:2529–2537. 2010. View Article : Google Scholar : PubMed/NCBI
20	Gutierrez A, Kentsis A, Sanda T, Holmfeldt L, Chen SC, Zhang J, Protopopov A, Chin L, Dahlberg SE, Neuberg DS, et al: The BCL11B tumor suppressor is mutated across the major molecular subtypes of T-cell acute lymphoblastic leukemia. Blood. 118:4169–4173. 2011. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Wojtuszkiewicz A, Peters GJ, Van Woerden NL, Dubbelman B, Escherich G, Schmiegelow K, Sonneveld E, Pieters R, van de Ven PM, Jansen G, et al: Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia. J Hematol Oncol. 8:612015. View Article : Google Scholar : PubMed/NCBI
23	Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, et al: Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: A randomized phase II study. Br J Haematol. 169:672–682. 2015. View Article : Google Scholar : PubMed/NCBI
24	Iyer NS, Balsamo LM, Bracken MB and Kadan-Lottick NS: Chemotherapy-only treatment effects on long-term neurocognitive functioning in childhood ALL survivors: A review and meta-analysis. Blood. 126:346–353. 2015. View Article : Google Scholar : PubMed/NCBI
25	Eiser C, Stride CB, Vora A, Goulden N, Mitchell C, Buck G, Adams M and Jenney MEM; National Cancer Research Institute Childhood Leukaemia Sub-Group and UK Childhood Leukaemia Clinicians Network, : Prospective evaluation of quality of life in children treated in UKALL 2003 for acute lymphoblastic leukaemia: A cohort study. Pediatr Blood Cancer. 64:2017. View Article : Google Scholar : PubMed/NCBI
26	Rodríguez-Lirio A, Pérez-Yarza G, Fernández-Suárez MR, Alonso-Tejerina E, Boyano MD and Asumendi A: Metformin Induces cell cycle arrest and apoptosis in drug-resistant leukemia cells. Leuk Res Treatment. 2015:5164602015.PubMed/NCBI
27	Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, Richter-Pechanska P, Marovca B, Pail O, Jenni S, et al: Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia. Blood. 129:e26–e37. 2017. View Article : Google Scholar : PubMed/NCBI
28	Lee DA: Cellular therapy: Adoptive immunotherapy with expanded natural killer cells. Immunol Rev. 290:85–99. 2019. View Article : Google Scholar : PubMed/NCBI
29	Idris SZ, Hassan N, Lee LJ, Md Noor S, Osman R, Abdul-Jalil M, Nordin AJ and Abdullah M: Increased regulatory T cells in acute lymphoblastic leukaemia patients. Hematology. 21:206–212. 2016. View Article : Google Scholar : PubMed/NCBI
30	Locatelli F, Moretta F, Brescia L and Merli P: Natural killer cells in the treatment of high-risk acute leukaemia. Semin Immunol. 26:173–179. 2014. View Article : Google Scholar : PubMed/NCBI
31	Atkins MB: Interleukin-2: Clinical applications. Semin Oncol. 29 (3 Suppl 7):S12–S17. 2002. View Article : Google Scholar
32	Terwijn M, Feller N, van Rhenen A, Kelder A, Westra G, Zweegman S, Ossenkoppele G and Schuurhuis GJ: Interleukin-2 receptor alpha-chain (CD25) expression on leukaemic blasts is predictive for outcome and level of residual disease in AML. Eur J Cancer. 45:1692–1699. 2009. View Article : Google Scholar : PubMed/NCBI
33	Cerny J, Yu H, Ramanathan M, Raffel GD, Walsh WV, Fortier N, Shanahan L, O'Rourke E, Bednarik J, Barton B, et al: Expression of CD25 independently predicts early treatment failure of acute myeloid leukaemia (AML). Br J Haematol. 160:262–266. 2013. View Article : Google Scholar : PubMed/NCBI
34	Du S, Jia Y, Tang H, Sun Y, Wu W, Sun L, Du J, Geng B, Tang C and Jin H: Immune regulation of hydrogen sulfide in children with acute lymphoblastic leukemia. Chin Med J (Engl). 127:3695–3699. 2014.PubMed/NCBI
35	Shen XH, Xu P, Yu X, Song HF, Chen H, Zhang XG, Wu MY and Wang XF: Discrepant clinical significance of CD28⁺CD8⁻ and CD4+CD25^high regulatory T cells during the progression of hepatitis B virus infection. Viral Immunol. 31:548–558. 2018. View Article : Google Scholar : PubMed/NCBI
36	Martkamchan S, Onlamoon N, Wang S, Pattanapanyasat K and Ammaranond P: The effects of anti-CD3/CD28 coated beads and IL-2 on expanded T cell for immunotherapy. Adv Clin Exp Med. 25:821–828. 2016. View Article : Google Scholar : PubMed/NCBI
37	Faganel Kotnik B, Grabnar I, Bohanec Grabar P, Dolzan V and Jazbec J: Association of genetic polymorphism in the folate metabolic pathway with methotrexate pharmacokinetics and toxicity in childhood acute lymphoblastic leukaemia and malignant lymphoma. Eur J Clin Pharmacol. 67:993–1006. 2011. View Article : Google Scholar : PubMed/NCBI
38	Kodidela S, Suresh Chandra P and Dubashi B: Pharmacogenetics of methotrexate in acute lymphoblastic leukaemia: Why still at the bench level? Eur J Clin Pharmacol. 70:253–260. 2014. View Article : Google Scholar : PubMed/NCBI
39	Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L, Huantes S, Loh M, Conway EM, Kang ES, et al: Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood. 118:2191–2199. 2011. View Article : Google Scholar : PubMed/NCBI
40	Lopez-Lopez E, Gutierrez-Camino A, Bilbao-Aldaiturriaga N, Pombar-Gomez M, Martin-Guerrero I and Garcia-Orad A: Pharmacogenetics of childhood acute lymphoblastic leukemia. Pharmacogenomics. 15:1383–1398. 2014. View Article : Google Scholar : PubMed/NCBI
41	Ansari M, Sauty G, Labuda M, Gagné V, Laverdière C, Moghrabi A, Sinnett D and Krajinovic M: Polymorphisms in multidrug resistance-associated protein gene 4 is associated with outcome in childhood acute lymphoblastic leukemia. Blood. 114:1383–1386. 2009. View Article : Google Scholar : PubMed/NCBI
42	Xin N, Fen Z, Li C, Yan X and Runming J: Intracranial hemorrhage following oral low-dose methotrexate after multiple toxicities caused by high-dose methotrexate in childhood acute lymphoblastic leukemia. Front Pharmacol. 10:10722019. View Article : Google Scholar : PubMed/NCBI
43	Gervasini G and Mota-Zamorano S: Clinical implications of methotrexate pharmacogenetics in childhood acute lymphoblastic leukaemia. Curr Drug Metab. 20:313–330. 2019. View Article : Google Scholar : PubMed/NCBI
44	Gonen N and Assaraf YG: Antifolates in cancer therapy: Structure, activity and mechanisms of drug resistance. Drug Resist Updat. 15:183–210. 2012. View Article : Google Scholar : PubMed/NCBI
45	Kager L, Cheok M, Yang W, Zaza G, Cheng Q, Panetta JC, Pui CH, Downing JR, Relling MV and Evans WE: Folate pathway gene expression differs in subtypes of acute lymphoblastic leukemia and influences methotrexate pharmacodynamics. J Clin Invest. 115:110–117. 2005. View Article : Google Scholar : PubMed/NCBI