title: Significance of expression of ITGA5 and its splice variants in acute myeloid leukemia: a report from the Children's Oncology Group.
abstract: Acute myeloid leukemia (AML) encompasses a heterogeneous group of diseases, and novel biomarkers for risk refinement and stratification are needed to optimize patient care. To identify novel risk factors, we performed transcriptome sequencing on 68 diagnostic AML samples and identified 2 transcript variants (-E2 and -E2/3) of the α-subunit (ITGA5) of the very late antigen-5 integrin. We then quantified expression of ITGA5 and these splice variants in specimens from participants of the AAML03P1 trial. We found no association between ITGA5 expression and clinical outcome. In contrast, patients with the highest relative expression (Q4) of the -E2/3 ITGA5 splice variant less likely had low-risk disease than Q1-3 patients (21% vs. 38%, P = 0.027). Q4 patients had worse response to chemotherapy with a higher proportion having persistent minimal residual disease (50% vs. 23%, P = 0.003) and inferior overall survival (at 5 years: 48% vs. 67%, P = 0.015); the latter association was limited to low-risk patients (Q4 vs. Q1-3: 56% vs. 85%, P = 0.043) and was not seen in standard-risk (51% vs. 60%, P = 0.340) or high-risk (33% vs. 38%, P = 0.952) patients. Our exploratory studies indicate that transcriptome sequencing is useful for biomarker discovery, as exemplified by the identification of ITGA5 -E2/3 splice variant as potential novel adverse prognostic marker for low-risk AML that, if confirmed, could serve to further risk-stratify this patient subset.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington.
authors.forename: Roland B
authors.initials: RB
authors.lastname: Walter
authors.forename: George S
authors.initials: GS
authors.lastname: Laszlo
authors.forename: Todd A
authors.initials: TA
authors.lastname: Alonzo
authors.forename: Robert B
authors.initials: RB
authors.lastname: Gerbing
authors.forename: Shawn
authors.initials: S
authors.lastname: Levy
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Fitzgibbon
authors.forename: Chelsea J
authors.initials: CJ
authors.lastname: Gudgeon
authors.forename: Rhonda E
authors.initials: RE
authors.lastname: Ries
authors.forename: Kimberly H
authors.initials: KH
authors.lastname: Harrington
authors.forename: Susana C
authors.initials: SC
authors.lastname: Raimondi
authors.forename: Betsy A
authors.initials: BA
authors.lastname: Hirsch
authors.forename: Alan S
authors.initials: AS
authors.lastname: Gamis
authors.forename: Martin
authors.initials: M
authors.lastname: W McIntosh
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D039482:Integrin alpha5 / Q000096:biosynthesis / Q000235:genetics; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008297:Male; D012326:RNA Splicing / Q000235:genetics*; D012307:Risk Factors; D015996:Survival Rate; D059467:Transcriptome / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D039482:Integrin alpha5