| Abstract: |
Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD +) have been implicated in the passive selection of ATRA-resistant acute promyelocytic leukemia clones leading to disease relapse.Among 45 relapse patients from the ATRA/chemotherapy arm of intergroup protocol C9710, 18 patients harbored PRα/LBD + (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD +. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD +), which were differentially associated with PRα/LBD + depending on ATRA treatment status at relapse: positively, On-ATRA; negatively, Off-ATRA. Thirteen of 21 patients (62%) had additional chromosome abnormalities (ACAs); all coanalyzed PRα/LBD mutant patients who relapsed off-ATRA (n = 5) had associated ACA. After relapse Off-ATRA, ACA and FLT3-ITD + were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD +, high, S-isoform. These exploratory results suggest that differing PRα/LBD + activities may interact with FLT3-ITD + or ACA, that FLT3-ITD + and ACA are associated with different intrinsic disease progression pathways manifest at relapse Off-ATRA, and that these different pathways may be short-circuited by ATRA-selectable defects at relapse On-ATRA. ACA and certain PRα/LBD + were also associated with reduced postrelapse survival. © 2012 by The American Society of Hematology. |
| Keywords: |
adolescent; adult; cancer survival; child; clinical article; preschool child; school child; aged; child, preschool; middle aged; survival analysis; gene mutation; mutation; disease course; antineoplastic agents; protein domain; genetic association; recurrence; drug resistance, neoplasm; chromosome aberration; leukemia, promyelocytic, acute; infant; disease progression; promyelocytic leukemia; oncogene proteins, fusion; leukocyte count; chromosome aberrations; leukemia relapse; karyotyping; retinoic acid; ligand binding; promyelocytic leukemia protein; retinoic acid receptor alpha; cd135 antigen; tretinoin; fms-like tyrosine kinase 3; internal tandem duplication mutation
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