Abstract
Childhood acute lymphoblastic leukemia survival rates have increased remarkably during last decades due, in part, to intensive treatment protocols. However, therapy resistance and toxicity are still two important barriers to survival. In this context, pharmacoepigenetics arises as a tool to identify new predictive markers, required to guide clinicians on risk stratification and dose individualization. The present study reviews current evidence about miRNA implication on childhood acute lymphoblastic leukemia therapy resistance and toxicity. A total of 12 studies analyzing differential miRNA expression in relation to drug resistance and six studies exploring the association between miRNAs-related SNPs and drug-induced toxicities were identified. We pointed out to miR-125b together with miR-99a and/or miR-100 overexpression as markers of vincristine resistance and rs2114358 in mir-1206 as mucositis marker as the most promising results.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Childhood cancer survival: a report from the United Kingdom Childhood Cancer Study. Cancer Epidemiol. 34(6), 659–666 (2010).
- 2 . Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics. Br. J. Haematol. 176(6), 867–882 (2017).
- 3 Childhood acute lymphoblastic leukemia: progress through collaboration. J. Clin. Oncol. 33(27), JCO.2014.59.1636 (2015).
- 4 . Acute lymphoblastic leukaemia. Lancet 381(9881), 1943–1955 (2013).
- 5 . Pharmacogenetics predictive of response and toxicity in acute lymphoblastic leukemia therapy. Blood Rev. 29(4), 243–249 (2015).
- 6 . Pharmacogenetics of childhood acute lymphoblastic leukemia. Pharmacogenomics 15(10), 1383–1398 (2014).
- 7 . Concepts in use of high-dose methotrexate therapy. Clin. Chem. 42(8 Pt 2), 1322–1329 (1996).
- 8 Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia. Pharmacogenomics J. 12(5), 379–385 (2012).
- 9 . Conventional compared with individualized chemotherapy for childhood acute lymphoblastic leukemia. N. Engl. J. Med. 338(8), 499–505 (1998).
- 10 . microRNAs and pharmacogenomics. Pharmacogenomics 11(5), 629–632 (2010).
- 11 . microRNA pharmacogenomics: post-transcriptional regulation of drug response. Trends Mol. Med. 17(8), 412–423 (2011). • An approach to understanding the miRNA role in drug efficacy and toxicity.
- 12 Mercaptopurine therapy intolerance and heterozygosity at the thiopurine S-methyltransferase gene locus. J. Natl Cancer Inst. 91(23), 2001–2008 (1999).
- 13 HLA-DRB1*07:01 is associated with a higher risk of asparaginase allergies. Blood 124(8), 1266–1276 (2014).
- 14 . Inherited genetic variation in childhood acute lymphoblastic leukemia. Blood. 125(26), 3988–3995 (2015).
- 15 . Pharmacogenetic predictors of treatment-related toxicity among children with acute lymphoblastic leukemia. Curr. Hematol. Malig. Rep. 12(3), 176–186 (2017).
- 16 Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J. Clin. Oncol. 27(35), 5972–5978 (2009).
- 17 Association of an inherited genetic variant with vincristine-related peripheral neuropathy in children with acute lymphoblastic leukemia. JAMA 313(8), 815–823 (2015).
- 18 Inherited NUDT15 variant is a genetic determinant of mercaptopurine intolerance in children with acute lymphoblastic leukemia. J. Clin. Oncol. 33(11), 1235–1242 (2015).
- 19 . Response to ‘PNPLA3 rs738409 and hepatotoxicity in children with B-cell acute lymphoblastic leukemia: a validation study in a Spanish cohort’. Clin. Pharmacol. Ther. 102(6), 907 (2017).
- 20 Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood 121(6), 898–904 (2013).
- 21 Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia. Br. J. Haematol. 171(1), 109–115 (2015).
- 22 . PNPLA3 rs738409 and hepatotoxicity in children with B-cell acute lymphoblastic leukemia: a validation study in a Spanish cohort. Clin. Pharmacol. Ther. 102(6), 906 (2017).
- 23 Polymorphisms of the SLCO1B1 gene predict methotrexate-related toxicity in childhood acute lymphoblastic leukemia. Pediatr. Blood Cancer. 57(4), 612–619 (2011).
- 24 Association of SLCO1B1 gene polymorphisms with toxicity response of high dose methotrexate chemotherapy in childhood acute lymphoblastic leukemia. Int. J. Clin. Exp. Med. 8(4), 6109–6113 (2015).
- 25 NUDT15 gene polymorphism related to mercaptopurine intolerance in Taiwan Chinese children with acute lymphoblastic leukemia. Pharmacogenomics J. 16(6), 536–539 (2016).
- 26 . Epigenetic mechanisms of importance for drug treatment. Trends Pharmacol. Sci. 35(8), 384–396 (2014). •• Review on epigenetic modifications in drug treatment success and egidrug concept.
- 27 . Pharmacoepigenetics: an element of personalized therapy? Expert Opin. Drug Metab. Toxicol. 13(4), 387–398 (2017).
- 28 . Pharmacoepigenetics and pharmacoepigenomics of gastrointestinal cancers. Expert Rev. Gastroenterol. Hepatol. 12(1), 1–14 (2017).
- 29 . Methyl-CpG-binding proteins in cancer: blaming the DNA methylation messenger. Biochem. Cell Biol. 83(3), 374–384 (2005).
- 30 DNA methylation profiling in doxorubicin treated primary locally advanced breast tumours identifies novel genes associated with survival and treatment response. Mol. Cancer 9(1), 68 (2010).
- 31 . Interplay between microRNAs and the epigenetic machinery: an intricate network. Biochim. Biophys. Acta 1799(10–12), 694–701 (2010).
- 32 Inhibition of histone deacetylation potentiates the evolution of acquired temozolomide resistance linked to MGMT upregulation in glioblastoma xenografts. Clin. Cancer Res. 18(15), 4070–4079 (2012).
- 33 . microRNA-based linkage between aging and cancer: from epigenetics view point. Cell J. 18(2), 117–126.
- 34 . Genetic variation in microRNA networks: the implications for cancer research. Nat. Rev. Cancer 10(6), 389–402 (2010).
- 35 . Novel classes of non-coding RNAs and cancer. J. Transl. Med. 10(1), 103 (2012).
- 36 . Pharmaco-miR: linking microRNAs and drug effects. Brief. Bioinform. 15(4), 648–659 (2014).
- 37 Anti-miR-21 oligonucleotide sensitizes leukemic K562 cells to arsenic trioxide by inducing apoptosis. Cancer Sci. 101(4), 948–954 (2010).
- 38 miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int. J. Cancer 123(2), 372–379 (2008).
- 39 Pharmacogenetics of microRNAs and microRNAs biogenesis machinery in pediatric acute lymphoblastic leukemia. PLoS ONE 9(3), e91261 (2014). • Study that finds the association between mir-1206 and mucositis.
- 40 microRNA characterize genetic diversity and drug resistance in pediatric acute lymphoblastic leukemia. Haematologica 96(5), 703–711 (2011). • Study that reveals the upregulation of miR-125b, miR-99a and miR-100 in vincristine and daunorubicin-resistant patients.
- 41 miR expression profiling at diagnosis predicts relapse in pediatric precursor B-cell acute lymphoblastic leukemia. Genes. Chromosomes Cancer 55(4), 328–339 (2016).
- 42 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. 20(24), 4903–4915 (2011).
- 43 Expression of certain leukemia/lymphoma related microRNAs and its correlation with prognosis in childhood acute lymphoblastic leukemia. Pathol. Oncol. Res. 21(3), 597–604 (2015).
- 44 Effect of microRNA-210 on prognosis and response to chemotherapeutic drugs in pediatric acute lymphoblastic leukemia. Cancer Sci. 105(4), 463–472 (2014).
- 45 Clinical significance of microRNA-34b expression in pediatric acute leukemia. Mol. Med. Rep. 13(3), 2777–2784 (2016).
- 46 . microRNA-185-5p restores glucocorticoid sensitivity by suppressing the mammalian target of rapamycin complex (mTORC) signaling pathway to enhance glucocorticoid receptor autoregulation. Leuk. Lymphoma 58(11), 2657–2667 (2017).
- 47 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. 162, 62–68 (2016).
- 48 . Upregulation of microRNA-21 is a poor prognostic marker in patients with childhood B cell acute lymphoblastic leukemia. Hematology 22(7), 392–397 (2017).
- 49 . miR-125b, miR-100 and miR-99a co-regulate vincristine resistance in childhood acute lymphoblastic leukemia. Leuk. Res. 37(10), 1315–1321 (2013). • Study that points out to the relation of miR-125b, miR-99a and miR-100 coexpression with vincristine resistance.
- 50 Expression of miR-196b is not exclusively MLL-driven but is especially linked to activation of HOXA genes in pediatric acute lymphoblastic leukemia. Haematologica 95(10), 1675–1682 (2010).
- 51 miR-125b predicts childhood acute lymphoblastic leukaemia poor response to BFM chemotherapy treatment. Br. J. Cancer 117(6), 801–812 (2017).
- 52 . miR-125b and miR-99a encoded on chromosome 21 co-regulate vincristine resistance in childhood acute megakaryoblastic leukemia. Hematol. Oncol. Stem Cell Ther. 8(2), 95–97 (2015).
- 53 Overcoming melanoma resistance to vemurafenib by targeting CCL2-induced miR-34a, miR-100 and miR-125b. Oncotarget 7(4), 4428–4441 (2016).
- 54 miR-125b and miR-100 are predictive biomarkers of response to induction chemotherapy in osteosarcoma. Sarcoma 2016, 1390571 (2016).
- 55 lncRNA miR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/β-catenin signaling. Nat. Med. 23(11), 1331–1341 (2017).
- 56 Inhibition of c-FLIPL expression by miRNA-708 increases the sensitivity of renal cancer cells to anti-cancer drugs. Oncotarget 7(22), 31832–31846 (2016).
- 57 . Restoration of microRNA-708 sensitizes ovarian cancer cells to cisplatin via IGF2BP1/Akt pathway. Cell Biol. Int. 41(10), 1110–1118 (2017).
- 58 microRNAs expression signatures are associated with lineage and survival in acute leukemias. Blood Cells. Mol. Dis. 44(3), 191–197 (2010).
- 59 microRNA signature in BCR-ABL1-like and BCR-ABL1-positive childhood acute lymphoblastic leukemia: similarities and dissimilarities. Leuk. Lymphoma 55(8), 1942–1945 (2014).
- 60 Discovery of new microRNAs by small RNAome deep sequencing in childhood acute lymphoblastic leukemia. Leukemia 25(9), 1389–1399 (2011).
- 61 Differential miRNA expression in childhood acute lymphoblastic leukemia and association with clinical and biological features. Leuk. Res. 36(3), 293–298 (2012).
- 62 . miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res. 42(Database issue), D68–D73 (2014).
- 63 Vincristine pharmacokinetics pathway and neurotoxicity during early phases of treatment in pediatric acute lymphoblastic leukemia. Pharmacogenomics 17(7), 731–741 (2016).
- 64 miR-pharmacogenetics of methotrexate in childhood B-cell acute lymphoblastic leukemia. Pharmacogenet. Genomics 26(11), 517–525 (2016).
- 65 The miR-1206 microRNA variant is associated with methotrexate-induced oral mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenet. Genomics 27, 303–306 (2017). • Study that replicates the association of miR-1206 and mucositis in a different cohort.
- 66 . Effects of a microRNA binding site polymorphism in SLC19A1 on methotrexate concentrations in Chinese children with acute lymphoblastic leukemia. Med. Oncol. 31(7), 62 (2014).
- 67 . Association between MTHFR microRNA binding site polymorphisms and methotrexate concentrations in Chinese pediatric patients with acute lymphoblastic leukemia. J. Gene Med. 19(11), e2990 (2017).
- 68 Genetic and metabolic determinants of methotrexate-induced mucositis in pediatric acute lymphoblastic leukemia. Pharmacogenomics J. 15(3), 248–254 (2015).
- 69 . MTHFR polymorphisms in childhood acute lymphoblastic leukemia: influence on methotrexate therapy. Pharmgenomics Pers. Med. 10, 69–78 (2017).
- 70 . Biology of the major facilitative folate transporters SLC19A1 and SLC46A1. Curr. Top. Membr. 73, 175–204 (2014).
- 71 . microRNA polymorphisms as markers of risk, prognosis and treatment response in hematological malignancies. Crit. Rev. Oncol. Hematol. 93(1), 1–17 (2015).
- 72 . SNPs in microRNA binding sites as prognostic and predictive cancer biomarkers. Crit. Rev. Oncog. 18(4), 327–340 (2013).
- 73 . A miR-24 microRNA binding-site polymorphism in dihydrofolate reductase gene leads to methotrexate resistance. Proc. Natl. Acad. Sci. USA 104(33), 13513–13518 (2007).
- 74 . microRNA as tools and therapeutics in lung cancer. Respir. Med. 109(7), 803–812 (2015).
- 75 . First microRNA mimic enters clinic. Nat. Biotechnol. 31(7), 577 (2013).
- 76 Phase I study of MRX34, a liposomal miR-34a mimic, administered twice weekly in patients with advanced solid tumors. Invest. New Drugs 35(2), 180–188 (2017).
- 77 . Non-coding RNAs: the cancer genome dark matter that matters! Clin. Chem. Lab. Med. 55(5), 705–714 (2017).
- 78 A significant metabolic and radiological response after a novel targeted microRNA-based treatment approach in malignant pleural mesothelioma. Am. J. Respir. Crit. Care Med. 191(12), 1467–1469 (2015).
- 79 . Correlation of long non-coding RNA expression with metastasis, drug resistance and clinical outcome in cancer. Oncotarget 5(18), 8027–8038 (2014). • Role of long-noncoding RNAs, in drug response, other epigenetic mechanism that offer a promising field to avoid drug resistance.
- 80 . Development of cytotoxicity-sensitive human cells using overexpression of long non-coding RNAs. J. Biosci. Bioeng. 119(5), 604–608 (2015).
- 81 Long noncoding RNA RP11-838N2.4 enhances the cytotoxic effects of temozolomide by inhibiting the functions of miR-10a in glioblastoma cell lines. Oncotarget 7(28), 43835–43851 (2016).
- 82 Association between well-characterized lung cancer lncRNA polymorphisms and platinum-based chemotherapy toxicity in Chinese patients with lung cancer. Acta Pharmacol. Sin. 38(4), 581–590 (2017).
- 83 . Knockdown of long non-coding RNA prostate cancer-associated ncRNA transcript 1 inhibits multidrug resistance and c-Myc-dependent aggressiveness in colorectal cancer Caco-2 and HT-29 cells. Mol. Cell. Biochem.
doi:10.1007/s11010-017-3177-8 (2017) (Epub ahead of print). - 84 MALAT1 is associated with poor response to oxaliplatin-based chemotherapy in colorectal cancer patients and promotes chemoresistance through EZH2. Mol. Cancer Ther. 16(4), 739–751 (2017).
- 85 A childhood acute lymphoblastic leukemia-specific lncRNA implicated in prednisolone resistance, cell proliferation, and migration. Oncotarget 8(5), 7477–7488 (2017).
- 86 Long non-coding RNA GAS5 polymorphism predicts a poor prognosis of acute myeloid leukemia in Chinese patients via affecting hematopoietic reconstitution. Leuk. Lymphoma 58(8), 1948–1957 (2017).
- 87 . The past, present and future of pharmacoepigenomics. Pharmacogenomics 11(5), 625–627 (2010).
- 88 PubMed. www.ncbi.nlm.nih.gov/pubmed