HOX gene expression in phenotypic and genotypic subgroups and low HOXA gene expression as an adverse prognostic factor in pediatric ALL.
BACKGROUND
HOX genes play an important role in both normal lymphopoiesis and leukemogenesis. However, HOX expression patterns in leukemia cells compared to normal lymphoid progenitors have not been systematically studied in acute lymphoblastic leukemia (ALL) subtypes.


METHODS
The RNA expression levels of HOXA, HOXB, and CDX1/2 genes were analyzed by qRT-PCR in a cohort of 61 diagnostic pediatric ALL samples and FACS-sorted subpopulations of normal lymphoid progenitors.


RESULTS
The RNA expression of HOXA7-10, HOXA13, and HOXB2-4 genes was exclusively detected in leukemic cells and immature progenitors. The RNA expression of HOXB6 and CDX2 genes was exclusively detected in leukemic cells but not in B-lineage cells at any of the studied developmental stages. HOXA3-4, HOXA7, and HOXB3-4 genes were differentially expressed between BCP-ALL and T-ALL subgroups, and among genotypically defined MLL/AF4, TEL/AML1, BCR/ABL, hyperdiploid and normal karyotype subgroups. However, this differential expression did not define specific clusters in hierarchical cluster analysis. HOXA7 gene was low expressed at the RNA level in patients with hyperdiploid leukemia, whereas HOXB7 and CDX2 genes were low expressed in TEL/AML1-positive and BCR/ABL-positive cases, respectively. In contrast to previous findings in acute myeloid leukemia, high HOXA RNA expression was associated with an excellent prognosis in Cox's regression model (P = 0.03). In MLL/AF4-positive ALL, lower HOXA RNA expression correlated with the methylation status of their promoters.


CONCLUSIONS
HOX gene RNA expression cannot discriminate leukemia subgroups or relative maturity of leukemic cells. However, HOXA RNA expression correlates with prognosis, and particular HOX genes are expressed in specific genotypically characterized subgroups.
Starkova
Julia
J
CLIP, Childhood Leukaemia Investigation Prague, 2nd Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. julia.starkova@lfmotol.cuni.cz
Zamostna
Blanka
B
Mejstrikova
Ester
E
Krejci
Roman
R
Drabkin
Harry A
HA
Trka
Jan
J
D000071616:CDX2 Transcription Factor; D002648:Child; D019175:DNA Methylation; D015973:Gene Expression Regulation, Leukemic / Q000502:physiology*; D005838:Genotype; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics*
C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; C086061:HOXB2 protein, human; C090460:HOXB4 protein, human; D018398:Homeodomain Proteins; C542921:HoxB3 protein, human; D014157:Transcription Factors; C088144:HoxA protein