Elevated blood MxA protein levels in children with newly diagnosed B-ALL: A prospective case-control study
Keywords:
MxA, Blood, Acute Lymphoblastic Leukemia, ChildrenAbstract
Background/Aim: Although leukemia is thought to be triggered or initiated by viral infections, it is not clear which viruses are the causative agents for which stage of the disease. Previous studies have shown that the MxA protein is expressed from blood mononuclear cells in reply to inducement of type I interferons in viral infections. Viral infections may trigger childhood B-cell acute lymphoblastic leukemia (B-ALL), and the hypothesis of this study was the detection of the presence of viral infection by measuring MxA expression in blood mononuclear cells of recently diagnosed pediatric B-ALL patients as a surrogate viral marker. Methods: This study consisted two groups; the study group consisted of 30 newly diagnosed B-ALL and the control group consisted of 29 healthy asymptomatic children of similar age. Proven bacterial infection and COVID-19 PCR positivity were exclusion criteria. Bacterial culture of peripheral blood, complete blood count, plasma CRP levels and whole blood MxA levels detected by ELISA (Enzyme-Linked ImmunoSorbent Assay) method were taken. Results: The patients’ mean age was 7.42 years in the leukemia group (previously mentioned as study group) and 7.25 years in the control group. Routine serologic studies for newly diagnosed leukemia patients (CMV, EBV VCA and Hepatitis B IgM, anti-HCV and anti-HIV) were negative in all patients without any bacterial infection detected. The MxA levels were found significantly higher in children with B-ALL than in control group (5.84 (2.18-199.38) and 2.45 (1.17-88.65) ngr/ml, respectively, with P<0.001). CRP levels were significantly elevated in children with B-ALL than the control group (27.40 (2.60-133.40) and 0.60 (0.12-4.90) mgr/L, respectively, with P<0.001). Conclusion: Our study demonstrates that blood MxA levels are increased in children with newly diagnosed B-ALL when compared to healthy asymptomatic children. This study is the first in literature in testing MxA levels in children with B-ALL. This finding may underline the triggering effect of viral infections in the onset of leukemia
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Inaba H, Greaves M, Mullighan CG. Acute lymphoblastic leukaemia. Lancet. 2013;381:1943-55.
Whitehead TP, Metayer C, Wiemels JL, Singer AW, Miller MD. Childhood Leukemia and Primary Prevention. Curr Probl Pediatr Adolesc Health Care. 2016 Oct;46(10):317-52.
Metayer C, Colt JS, Buffler PA, Reed HD, Selvin S, Crouse V, et al. Exposure to herbicides in house dust and risk of childhood acute lymphoblastic leukemia. Journal of exposure science & environmental epidemiology. 2013 Jul;23(4):363–70.
Carlos-Wallace FM, Zhang L, Smith MT, Rader G, Steinmaus C. Parental, In Utero, and Early-Life Exposure to Benzene and the Risk of Childhood Leukemia: A Meta-Analysis. Am J Epidemiol. 2016 Jan 1;183(1):1–14.
Filippini T, Heck JE, Malagoli C, Del Giovane C, Vinceti M. A review and meta-analysis of outdoor air pollution and risk of childhood leukemia. J Environ Sci Health C Environ Carcinog Ecotoxicol Rev. 2015;33(1):36-66.
Greenland S, Sheppard AR, Kaune WT, Poole C, Kelsh MA. A pooled analysis of magnetic fields, wire codes, and childhood leukemia. Childhood Leukemia-EMF Study Group. Epidemiology (Cambridge, Mass). 2000 Nov 11;(6):624–34.
Petridou E, Ntouvelis E, Dessypris N, Terzidis A, Trichopoulos D, Childhood Hematology-Oncology Group. Maternal diet and acute lymphoblastic leukemia in young children. Cancer Epidemiol Biomarkers Prev. 2005 Aug;14(8):1935–39.
Buckley JD, Buckley CM, Ruccione K, Sather HN, Waskerwitz MJ, Woods WG, Robison LL. Epidemiological characteristics of childhood acute lymphocytic leukemia. Analysis by immunophenotype. The Childrens Cancer Group. Leukemia. 1994 May;8(5):856-64.
Chan LC, Lam TH, Li CK, Lau YL, Li CK, Yuen HL, Lee CW, Ha SY, Yuen PM, Leung NK, Patheal SL, Greaves MF, Alexander FE. Is the timing of exposure to infection a major determinant of acute lymphoblastic leukaemia in Hong Kong? Paediatr Perinat Epidemiol. 2002 Apr;16(2):154-65.
Ward G. The infective theory of acute leukemia. Br J Child Dis. 1917;14:10–20.
Greaves MF. Speculations on the cause of childhood acute lymphoblastic leukemia. Leukemia. 1988 Feb;2(2):120-5.
Kinlen L. Evidence for an infective cause of childhood leukaemia: comparison of a Scottish new town with nuclear reprocessing sites in Britain. Lancet. 1988 Dec 10;2(8624):1323-7.
Crouch S, Lightfoot T, Simpson J, Smith A, Ansell P, Roman E. Infectious illness in children subsequently diagnosed with acute lymphoblastic leukemia: modeling the trends from birth to diagnosis. Am J Epidemiol. 2012 Sep 1;176(5):402-8.
Chang JS, Tsai CR, Tsai YW, Wiemels JL. Medically diagnosed infections and risk of childhood leukaemia: a population-based case-control study. International journal of epidemiology. 2012 Aug;41(4):1050-9.
Fidanza M, Seif AE, DeMicco A, Rolf N, Jo S, Yin B, et al. Inhibition of precursor B-cell malignancy progression by toll-like receptor ligand-induced immune responses. Leukemia. 2016 Oct;30(10):2116-9.
Fidanza M, Seif AE, Jo S, Kariminia A, Rolf N, Sly LM, et al. IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life. Eur J Immunol. 2017 May;47(5):892-9.
Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, Auer F, González-Herrero I, García-Ramírez I, et al. Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility. Cancer Discov. 2015 Dec;5(12):1328-43. doi: 10.1158/2159-8290.CD-15-0892. Epub 2015 Sep 25.
Rodríguez-Hernández G, Hauer J, Martín-Lorenzo A, Schäfer D, Bartenhagen C, García-Ramírez I, et al. Infection Exposure Promotes ETV6-RUNX1 Precursor B-cell Leukemia via Impaired H3K4 Demethylases. Cancer Res. 2017 Aug 15;77(16):4365-77. doi: 10.1158/0008-5472.CAN-17-0701. Epub 2017 Jun 19.
Swaminathan S, Müschen M. Infectious origins of childhood leukemia. Oncotarget. 2015 Jul 10;6(19):16798-9.
Smith M. Considerations on a possible viral etiology for B-precursor acute lymphoblastic leukemia of childhood. J Immunother. 1997 Mar;20(2):89-100.
Smith MA, Simon R, Strickler HD, McQuillan G, Ries LA, Linet MS. Evidence that childhood acute lymphoblastic leukemia is associated with an infectious agent linked to hygiene conditions. Cancer Causes Control. 1998 May;9(3):285-98.
Kinlen LJ. Epidemiological evidence for an infective basis in childhood leukaemia. Br J Cancer. 1995 Jan;71(1):1-5.
Toivonen L, Schuez-Havupalo L, Rulli M, Ilonen J, Pelkonen J, et al. Blood MxA protein as a marker for respiratory virus infections in young children. J Clin Virol. 2015 Jan;62:8-13.
Engelmann I, Dubos F, Lobert PE, Houssin C, Degas V, Sardet A, et al. Diagnosis of viral infections using myxovirus resistance protein A (MxA). Pediatrics. 2015 Apr;135(4):e985-93.
Ivaska L, Niemelä J, Lempainen J, Österback R, Waris M, Vuorinen T, Hytönen J, Rantakokko-Jalava K, Peltola V. Aetiology of febrile pharyngitis in children: Potential of myxovirus resistance protein A (MxA) as a biomarker of viral infection. J Infect. 2017 Apr;74(4):385-92.
Ronni T, Melén K, Malygin A, Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol. 1993 Mar 1;150(5):1715-26.
Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J Interferon Cytokine Res. 2011 Jan;31(1):79-87.
Cobaleda C, Vicente-Dueñas C, Sanchez-Garcia I. Infectious triggers and novel therapeutic opportunities in childhood B cell leukaemia. Nat Rev Immunol. 2021;21:570–81.
Swaminathan S, Muschen M. Infectious origins of childhood leukemia. Oncotarget. 2015;6:16798–99.
Greaves, M. A causal mechanism for childhood acute lymphoblastic leukaemia. Nat Rev Cancer. 2018;18:471–84.
Francis SS, Selvin S, Yang W, Buffler PA, Wiemels JL. Unusual space-time patterning of the Fallon, Nevada leukemia cluster: evidence of an infectious etiology. Chem Biol Interact. 2012;196:102–9.
Fidanza M, Seif AE, Jo S, Kariminia A, Rolf N, Sly LM, Grupp SA, Reid GSD. IFN-γ directly inhibits murine B-cell precursor leukemia-initiating cell proliferation early in life. Eur J Immunol. 2017 May;47(5):892-9.
Martín-Lorenzo A, Hauer J, Vicente-Dueñas C, Auer F, González-Herrero I, García-Ramírez I, et al. Infection Exposure is a Causal Factor in B-cell Precursor Acute Lymphoblastic Leukemia as a Result of Pax5-Inherited Susceptibility. Cancer Discov. 2015 Dec;5(12):1328-43.
Chieux V, Hober D, Chehadeh W, Harvey J, Alm G, Cousin J, et al. MxA protein in capillary blood of children with viral infections. J Med Virol. 1999 Dec;59(4):547-51.
Ronni T, Melén K, Malygin A, Julkunen I. Control of IFN-inducible MxA gene expression in human cells. J Immunol. 1993 Mar 1;150(5):1715-26.
Yoshimasu T, Manabe A, Ebihara Y, Tanaka R, Ooi J, Iseki T, et al. MxA expression in patients with viral infection after allogeneic stem cell transplantation. Bone Marrow Transplant. 2003 Aug;32(3):313-6.
Roers A, Hochkeppel HK, Horisberger MA, Hovanessian A, Haller O. MxA gene expression after live virus vaccination: a sensitive marker for endogenous type I interferon. J Infect Dis. 1994 Apr;169(4):807-13.
Forster J, Schweizer M, Schumacher RF, Kaufmehl K, Lob S. MxA protein in infants and children with respiratory tract infection. Acta Paediatr. 1996 Feb;85(2):163-7.
Halminen M, Ilonen J, Julkunen I, Ruuskanen O, Simell O, Mäkelä MJ. Expression of MxA protein in blood lymphocytes discriminates between viral and bacterial infections in febrile children. Pediatr Res. 1997 May;41(5):647-50.
Chieux V, Hober D, Harvey J, Lion G, Lucidarme D, Forzy G, Duhamel M, Cousin J, Ducoulombier H, Wattré P. The MxA protein levels in whole blood lysates of patients with various viral infections. J Virol Methods. 1998 Feb;70(2):183-91.
Meier V, Mihm S, Ramadori G. MxA gene expression in peripheral blood mononuclear cells from patients infected chronically with hepatitis C virus treated with interferon-alpha. J Med Virol. 2000 Nov;62(3):318-26.
Koskenvuo MM, Halminen M, Blomqvist M, Vainionpää R, Ilonen J, Julkunen I, Salmi TT, Mäkelä MJ. Expression of MxA protein in blood lymphocytes of children receiving anticancer chemotherapy. Pediatr Hematol Oncol. 2006 Dec;23(8):649-60.
Manabe A, Yoshimasu T, Ebihara Y, Yagasaki H, Wada M, Ishikawa K, Hara J, Koike K, Moritake H, Park YD, Tsuji K, Nakahata T; MDS Committee of the Japanese Society of Pediatric Hematology. Viral infections in juvenile myelomonocytic leukemia: prevalence and clinical implications. J Pediatr Hematol Oncol. 2004 Oct;26(10):636-41.
Vallittu AM, Halminen M, Peltoniemi J, Ilonen J, Julkunen I, Salmi A, Erälinna JP; Finnish Beta-Interferon Study Group. Neutralizing antibodies reduce MxA protein induction in interferon-beta-1a-treated MS patients. Neurology. 2002 Jun 25;58(12):1786-90.
Maria NI, Brkic Z, Waris M, van Helden-Meeuwsen CG, Heezen K, van de Merwe JP, et al. MxA as a clinically applicable biomarker for identifying systemic interferon type I in primary Sjogren's syndrome. Ann Rheum Dis. 2014 Jun;73(6):1052-9.
Steel DM, Whitehead AS. The major acute phase reactants: C-reactive protein, serum amyloid P component and serum amyloid A protein. Immunol Today. 1994 Feb;15(2):81-8.
Husain TM, Kim DH. C-Reactive Protein and Erythrocyte Sedimentation Rate in Orthopaedics. The University of Pennsylvania Orthopaedic Journal. 2002;15:13–6.
Shimony S, Rozovski U, Sudry N, Yeshurun M, Yahav D, Raanani P, et al. Early detection of infectious complications during induction therapy for acute leukemia with serial C-reactive protein biomarker assessment. Leuk Lymphoma. 2020 Nov;61(11):2708-13.
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