title: Impact of promoter polymorphisms in key regulators of the intrinsic apoptosis pathway on the outcome of childhood acute lymphoblastic leukemia.
abstract: The introduction of multiagent treatment protocols has led to a remarkable increase in survival rates for children diagnosed with acute lymphoblastic leukemia, yet for a subpopulation of patients, resistance to chemotherapeutics remains an obstacle to successful treatment. Here we investigate the role of the mitochondrial (or intrinsic) apoptosis pathway in modulating the onset and outcomes of childhood acute lymphoblastic leukemia. Cell death is a highly regulated process that plays an essential role in regulating cell homeostasis, particularly in tissues with high intrinsic proliferating capacity such as the hematopoietic system. Following the underlying paradigm that cis-acting genetic variation can influence disease risk and outcomes by modulating gene expression, we performed a systematic analysis of the proximal promoter regions of 21 genes involved in apoptosis. Using gene reporter assays, we show that promoter variations in 11 intrinsic apoptosis genes, including ADPRT, APAF1, BCL2, BAD, BID, MCL1, BIRC4, BCL2L1, ENDOG, YWHAB, and YWHAQ, influence promoter activity in an allele-specific manner. We also show that correlated promoter variation and increased expression of MCL1 is associated with reduced overall survival among high-risk patients receiving higher doses of corticosteroid, suggesting that increased expression of this anti-apoptosis gene could lead to reduced cell death and influence treatment response in a disease- and dose-responsive manner.
authors.affiliation: daniel.sinnett@umontreal.ca.
authors.forename: Rocio
authors.initials: R
authors.lastname: Sanchez
authors.forename: Janick
authors.initials: J
authors.lastname: St-Cyr
authors.forename: Marie-Eve
authors.initials: ME
authors.lastname: Lalonde
authors.forename: Jasmine
authors.initials: J
authors.lastname: Healy
authors.forename: Chantal
authors.initials: C
authors.lastname: Richer
authors.forename: Vincent
authors.initials: V
authors.lastname: Gagné
authors.forename: Caroline
authors.initials: C
authors.lastname: Laverdière
authors.forename: Lewis B
authors.initials: LB
authors.lastname: Silverman
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Sallan
authors.forename: Donna
authors.initials: D
authors.lastname: Neuberg
authors.forename: Jeffery L
authors.initials: JL
authors.lastname: Kutok
authors.forename: Ekaterini A
authors.initials: EA
authors.lastname: Kritikou
authors.forename: Maja
authors.initials: M
authors.lastname: Krajinovic
authors.forename: Daniel
authors.initials: D
authors.lastname: Sinnett
mesh_terms: D000293:Adolescent; D000328:Adult; D017209:Apoptosis / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality
chemical_list: D051017:Apoptosis Regulatory Proteins; D009363:Neoplasm Proteins
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