title: Gene expression profiling in the leukemic stem cell-enriched CD34+ fraction identifies target genes that predict prognosis in normal karyotype AML.
abstract: In order to identify acute myeloid leukemia (AML) CD34(+)-specific gene expression profiles, mononuclear cells from AML patients (n=46) were sorted into CD34(+) and CD34(-) subfractions, and genome-wide expression analysis was performed using Illumina BeadChip Arrays. AML CD34(+) and CD34(-) gene expression was compared with a large group of normal CD34(+) bone marrow (BM) cells (n=31). Unsupervised hierarchical clustering analysis showed that CD34(+) AML samples belonged to a distinct cluster compared with normal BM and that in 61% of the cases the AML CD34(+) transcriptome did not cluster together with the paired CD34(-) transcriptome. The top 50 of AML CD34(+)-specific genes was selected by comparing the AML CD34(+) transcriptome with the AML CD34(-) and CD34(+) normal BM transcriptomes. Interestingly, for three of these genes, that is, ankyrin repeat domain 28 (ANKRD28), guanine nucleotide binding protein, alpha 15 (GNA15) and UDP-glucose pyrophosphorylase 2 (UGP2), a high transcript level was associated with a significant poorer overall survival (OS) in two independent cohorts (n=163 and n=218) of normal karyotype AML. Importantly, the prognostic value of the continuous transcript levels of ANKRD28 (OS hazard ratio (HR): 1.32, P=0.008), GNA15 (OS HR: 1.22, P=0.033) and UGP2 (OS HR: 1.86, P=0.009) was shown to be independent from the well-known risk factors FLT3-ITD, NPM1c(+) and CEBPA mutation status.
authors.affiliation: Department of Experimental Hematology, Division of Pediatric Oncology/Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: H J M
authors.initials: HJ
authors.lastname: de Jonge
authors.forename: C M
authors.initials: CM
authors.lastname: Woolthuis
authors.forename: A Z
authors.initials: AZ
authors.lastname: Vos
authors.forename: A
authors.initials: A
authors.lastname: Mulder
authors.forename: E
authors.initials: E
authors.lastname: van den Berg
authors.forename: P M
authors.initials: PM
authors.lastname: Kluin
authors.forename: K
authors.initials: K
authors.lastname: van der Weide
authors.forename: E S J M
authors.initials: ES
authors.lastname: de Bont
authors.forename: G
authors.initials: G
authors.lastname: Huls
authors.forename: E
authors.initials: E
authors.lastname: Vellenga
authors.forename: J J
authors.initials: JJ
authors.lastname: Schuringa
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics*; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology*; D011379:Prognosis; D012307:Risk Factors; D055815:Young Adult
chemical_list: D018952:Antigens, CD34; D014408:Biomarkers, Tumor