HOX Genes Expression Pattern Is Related to Phenotypical and Genotypical Subgroups but Not to Treatment Response in Pediatric ALL.

Abstract 1288

Poster Board I-310

Homeodomain (HOX) genes encode transcription factors important for embryonic development. They are involved in normal hemopoiesis regulation and likely also in leukemogenesis as a result of translocations and other aberrations present in leukemias. In previous work Drabkin et al. demonstrated that HOX gene expression patterns differentiate major cytogenetic groups in acute myeloid leukemias. In this study we focused on HOX gene expression in pediatric acute lymphoblastic leukemias (ALL). We were interested if certain HOX genes or expression pattern could distinguish subpopulations of ALL. We analyzed the expression pattern of 21 HOX genes from HOXA and HOXB clusters and non-cluster HOX genes, CDX1 and CDX2 using qRT-PCR approach. We looked at 54 patients chosen according to phenotypic (T-ALL, BCP-ALL), prognostic (PGR – prednisone good responders, PPR – prednisone poor responders) and genotypic (BCR/ABL, MLL/AF4, TEL/AML1, hyperdiploid) characteristics.

Overall analysis comparing all studied groups showed that HOXA7 (Kruskal-Wallis test p=0.000045), HOXA3 (p=0.000098), HOXB3 (p=0.00015), HOXA4 (p=0.000619) and HOXB4 (p=0.001925) genes were differently expressed among groups. Wilcoxon signed-rank test, a non-parametric statistical analysis comparing two groups against each other, showed that HOXA3, A4 and B3 distinguish BCP-ALL (w/o fusion gene) and T-ALL. Interestingly, particular HOX genes expression showed significant difference among the groups: HOXA7 gene is significantly downregulated in hyperdiploid ALL (p=0.03) compared to all other subgroups. Furthermore, HOXB7 gene is specifically upregulated in TEL/AML-positive patients (p=0.0048 vs BCP-ALL w/o fusion gene) and CDX2 is downregulated in BCR/ABL-positive patients (p=0.001 vs hyperdiploid; p=0.006 vs TEL/AML1; p=0.03 vs MLL/AF4). Suprisingly, TEL/AML1-positive patients have similar expression of HOXA1-A4 as T-ALL patients. HOX genes expression pattern seemed to differ in MLL/AF4-positive patients according to the age at diagnosis. Three patients younger than 2 months at presentation clustered together in clear contrast to the MLL/AF4-positive patient diagnosed at the age of 13 years with secALL who presented with very low overall expression of all HOX genes. Next, we looked for diversity and similarity between groups. We determined how many HOX genes were expressed differently (p<0.05) and similarly (p=1.0) between particular ALL subtypes. The most outlying couples were T-ALL vs PPR (11 genes differently expressed), T-ALL vs PGR (9 genes) and T-ALL vs TEL/AML1 (6 genes). In contrast, the closest groups were BCR/ABL vs PPR, MLL/AF4 vs T-ALL and MLL/AF4 vs PPR.

Our data demonstrate that BCP-ALL (w/o known fusion gene) can be distinguished from T-ALL by the HOX gene expression (in particular HOXA3, HOXB3, HOXA4). Like in AML, expression pattern differs also among the major cytogenetical subgroups of ALL. On the other hand, within the BCP-ALL subgroup, no expression difference was found between patients with good (PGR) and poor (PPR) response to the initial steroid therapy which is known to be an excellent predictor of outcome. HOX genes of interest emerged from our analysis: low expression of HOXA7 in hyperdiploid ALL, highly expressed HOXB7 in TEL/AML1-positive ALL and specifically downregulated CDX2 in BCR/ABL-positive ALL. Age-related differences in expression in MLL/AF4-positive ALL seem to link the expression pattern rather with the relative maturity of the cell undergoing (pre)malignant transformation than with the specific changes caused by the leukemogenesis itself. This hypothesis must be tested in comparison to the HOX genes expression in sorted subtypes of normal T and B precursors.

This work was supported by MSM0021620813, IGA NR/9526 and GACR 301/08/P532.