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High mTOR expression independently prognosticates poor clinical outcome to induction chemotherapy in acute lymphoblastic leukemia

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Abstract

In acute lymphoblastic leukemia (ALL), limited data are available on mTOR gene expression in clinical samples and its role in predicting response to induction chemotherapy. mRNA expression of mTOR gene was determined quantitatively by real-time PCR in 50 ALL patients (30 B-ALL and 20 T-ALL) and correlated with clinical outcome after induction chemotherapy. Expression level of mTOR was upregulated in more than 50% of cases of ALL. In T-ALL, high expression of mTOR was commonly seen, more in adults than children (82 vs. 55% cases), while in B-ALL it was same (~ 63% cases) in both adults and children. Mean fold change of mTOR expression was significantly higher in non-responders compared to responders of both adult B-ALL (7.4 vs. 2.7, p = 0.05) and T-ALL (13.9 vs. 2.4, p = 0.001). Similar results were seen in pediatric non-responders when compared to responders of both B-ALL (14.5 vs. 2.5, p = 0.006) and T-ALL (24.2 vs. 1.7, p = 0.002). Interestingly, we have observed that mTOR expression was two times higher in non-responders of children compared to adults in both B-ALL (14.5 vs. 7.4, p = 0.05) and T-ALL (24.2 vs. 13.9, p = 0.01). Multivariate analysis with other known prognostic factors revealed that mTOR expression independently predicts clinical response to induction chemotherapy in ALL. This study demonstrates that high mTOR expression is associated with poor clinical outcome in ALL and can serve as a potential target for novel therapeutic strategies.

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References

  1. Center M, Siegel R, Jemal A. Global cancer facts and figures. Atlanta: American Cancer Society; 2011. p. 1–52.

    Google Scholar 

  2. Farhi DC, Rosenthal NS. Acute lymphoblastic leukemia. Clin Lab Med. 2000;20(1):17–28.

    CAS  PubMed  Google Scholar 

  3. Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29(5):532–43. doi:10.1200/JCO.2010.30.1382.

    Article  PubMed  Google Scholar 

  4. Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006;354(2):166–78. doi:10.1056/NEJMra052603.

    Article  CAS  PubMed  Google Scholar 

  5. Mukhopadhyay A, Gangopadhyay S, Dasgupta S, Paul S, Mukhopadhyay S, Ray UK. Surveillance and expected outcome of acute lymphoblastic leukemia in children and adolescents: an experience from Eastern India. Indian J Med Paediatr Oncol. 2013;34(4):280. doi:10.4103/0971-5851.125245.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Pópulo H, Lopes JM, Soares P. The mTOR signalling pathway in human cancer. Int J Mol Sci. 2012;13(2):1886–918. doi:10.3390/ijms13021886.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev. 2004;18(16):1926–45. doi:10.1101/gad.1212704.

    Article  CAS  PubMed  Google Scholar 

  8. Gazi M, Moharram SA, Marhäll A, Kazi JU. The dual specificity PI3K/mTOR inhibitor PKI-587 displays efficacy against T-cell acute lymphoblastic leukemia (T-ALL). Cancer Lett. 2017;28(392):9–16. doi:10.1016/j.canlet.2017.01.035.

    Article  Google Scholar 

  9. Granato M, Rizzello C, Romeo MA, et al. Concomitant reduction of c-Myc expression and PI3K/AKT/mTOR signaling by quercetin induces a strong cytotoxic effect against Burkitt’s lymphoma. Int J Biochem Cell Biol. 2016;31(79):393–400. doi:10.1016/j.biocel.2016.09.006.

    Article  Google Scholar 

  10. Janes MR, Vu C, Mallya S, et al. Efficacy of the investigational mTOR kinase inhibitor MLN0128/INK128 in models of B-cell acute lymphoblastic leukemia. Leukemia. 2013;27(3):586–94. doi:10.1038/leu.2012.276.

    Article  CAS  PubMed  Google Scholar 

  11. Saunders P, Cisterne A, Weiss J, Bradstock KF, Bendall LJ. The mammalian target of rapamycin inhibitor RAD001 (everolimus) synergizes with chemotherapeutic agents, ionizing radiation and proteasome inhibitors in pre-B acute lymphocytic leukemia. Haematologica. 2011;96(1):69–77. doi:10.3324/haematol.2010.026997.

    Article  CAS  PubMed  Google Scholar 

  12. Shi PJ, Xu LH, Lin KY, Weng WJ, Fang JP. Synergism between the mTOR inhibitor rapamycin and FAK down-regulation in the treatment of acute lymphoblastic leukemia. J Hematol Oncol. 2016;9(1):12. doi:10.1186/s13045-016-0241-x.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Nemes K, Sebestyén A, Márk Á, et al. Mammalian target of rapamycin (mTOR) activity dependent phospho-protein expression in childhood acute lymphoblastic leukemia (ALL). PLoS ONE. 2013;8(4):e59335. doi:10.1371/journal.pone.0059335.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Ulińska E, Mycko K, Sałacińska-Łoś E, et al. Impact of mTOR expression on clinical outcome in paediatric patients with B-cell acute lymphoblastic leukaemia–preliminary report. Contemp Oncol. 2016;20(4):291. doi:10.5114/wo.2016.61848.

    Google Scholar 

  15. Bhushan B, Chauhan PS, Saluja S, et al. Aberrant phenotypes in childhood and adult acute leukemia and its association with adverse prognostic factors and clinical outcome. Clin Exp Med. 2010;10(1):33–40. doi:10.1007/s10238-009-0067-8.

    Article  PubMed  Google Scholar 

  16. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2—ΔΔCT method. Methods. 2001;25(4):402–8. doi:10.1006/meth.2001.1262.

    Article  CAS  PubMed  Google Scholar 

  17. Cross NC, Melo JV, Feng L, Goldman JM. An optimized multiplex polymerase chain reaction (PCR) for detection of BCR-ABL fusion mRNAs in haematological disorders. Leukemia. 1994;8(1):186–9.

    CAS  PubMed  Google Scholar 

  18. Pui CH, Cheng C, Leung W, et al. Extended follow-up of long-term survivors of childhood acute lymphoblastic leukemia. N Engl J Med. 2003;349(7):640–9. doi:10.1056/NEJMoa035091.

    Article  PubMed  Google Scholar 

  19. Nachman JB, Heerema NA, Sather H, et al. Outcome of treatment in children with hypodiploid acute lymphoblastic leukemia. Blood. 2007;110(4):1112–5. doi:10.1182/blood-2006-07-038299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kamat DM, Gopal R, Advani SH, et al. Pattern of subtypes of acute lymphoblastic leukemia in India. Leuk Res. 1985;9(7):927–34. doi:10.1016/0145-2126(85)90315-7.

    Article  CAS  PubMed  Google Scholar 

  21. Bhargava M, Kumar R, Karak A, Kochupillai V, Arya LS, Mohanakumar T. Immunological subtypes of acute lymphoblastic leukemia in North India. Leuk Res. 1988;12(8):673–8. doi:10.1016/0145-2126(88)90102-6.

    Article  CAS  PubMed  Google Scholar 

  22. Medyouf H, Gusscott S, Wang H, et al. High-level IGF1R expression is required for leukemia-initiating cell activity in T-ALL and is supported by Notch signaling. J Exp Med. 2011;208(9):1809–22. doi:10.1084/jem.20110121.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Tasian SK, Doral MY, Borowitz MJ, et al. Aberrant STAT5 and PI3 K/mTOR pathway signaling occurs in human CRLF2-rearranged B-precursor acute lymphoblastic leukemia. Blood. 2012;120(4):833–42. doi:10.1182/blood-2011-12-389932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Jiang Z, Wu D, Lin S, Li P. CD34 and CD38 are prognostic biomarkers for acute B lymphoblastic leukemia. Biomark Res. 2016;4(1):23. doi:10.1186/s40364-016-0080-5.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cascavilla N, Musto P, D’Arena GI, Ladogana S, Matera R, Carotenuto M. Adult and childhood acute lymphoblastic leukemia: clinico-biological differences based on CD34 antigen expression. Haematologica. 1997;82(1):31–7.

    CAS  PubMed  Google Scholar 

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Funding

This study was supported by a grant from Department of Science and Technology (DST), Government of India.

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Authors and Affiliations

  1. National Institute of Pathology (ICMR), Safdarjung Hospital Campus, New Delhi, 110029, India

    Asheema Khanna, Pradeep Singh Chauhan, Sunita Saxena & Fouzia Siraj

  2. Symbiosis School of Biomedical Sciences, Symbiosis International University, Pune, Maharashtra, 412115, India

    Asheema Khanna

  3. Department of Medical Oncology, DR.B.R, Ambedkar Institute-Rotary Cancer Hospital, All India Institute of Medical Sciences, New Delhi, 110029, India

    Bharat Bhushan

  4. Department of Hematology, Safdarjung Hospital, New Delhi, India

    Dipendra Kumar Gupta

Authors
  1. Asheema Khanna
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  2. Bharat Bhushan
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  3. Pradeep Singh Chauhan
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  4. Sunita Saxena
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  5. Dipendra Kumar Gupta
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  6. Fouzia Siraj
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Contributions

AK designed the study, performed the experiments, drafted the paper and analyzed the data. BB analyzed the data. PSC helped in acquisition and interpretation of data. DKG contributed to diagnosis and treatment of patients. SS supervised the study and contributed to essential reagents and tools. FS designed the study, revised the paper and approved the final and submitted versions of the manuscript.

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Correspondence to Fouzia Siraj.

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The authors declare that they have no conflict of interest.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Khanna, A., Bhushan, B., Chauhan, P.S. et al. High mTOR expression independently prognosticates poor clinical outcome to induction chemotherapy in acute lymphoblastic leukemia. Clin Exp Med 18, 221–227 (2018). https://doi.org/10.1007/s10238-017-0478-x

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  • DOI: https://doi.org/10.1007/s10238-017-0478-x

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