HOX Expression Patterns Identify Major Cytogenetic Groups and Are of Prognostic Importance in Adult AML.

Naturally occurring and experimentally-induced deregulation of HOX genes has been causally linked to leukemia and myeloproliferative states. We developed and validated SYBR-green based real-time qRT-PCR assays for the clustered HOXA-D genes as well as other selected homeodomain, trithorax and polycomb genes. These were used to examine 120 cases of adult AML (median age 58 y) with the following cytogenetic classifications: favorable (FAV) 17, intermediate (INT) 53, unfavorable (UNFAV) 46, no analyzable metaphases 4, plus normal CD34+ sorted cells from 4 bone marrow donors. HOX expression patterns were intimately linked to the major cytogenetic subsets and provide a unifying feature for some AML subsets, particularly within the favorable prognostic group. Twenty genes were identified, with a 95% confidence of no false positives, that distinguished the major cytogenetic groups. In general, levels of HOXA genes and MEIS1 distinguished FAV vs. INT and FAV vs. UNFAV groups, while the HOXB and PBX3 levels distinguished either all three groups or INT vs. UNFAV. Comparing 68 patients who achieved a complete response with 49 patients who had resistant disease (or failed induction therapy), 11 genes were differentially expressed with parametric p-values < 0.05. Based on permutation distribution with a 95% confidence level, there were no more than 5 false positives among these 11 genes. Using a COX proportional hazards model and patients for whom survival data were available, HOXA9 and HOXA10 were predictive of overall survival, with parametric p-values <0.05. Lastly, compared to normal CD34+ cells, homeodomain gene expression was abnormal in nearly every AML. Based on these results and the role of HOX deregulation in experimental leukemogenesis, we propose that differences in HOX expression may be responsible for some of the biological differences observed among major cytogenetic subsets in human AML.