Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia
(2012) Blood — Vol. 120, n° 10, p. 2098-2108 (2012)
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- Mutations in the all-trans retinoic acid (ATRA)-targeted ligand binding domain of PML-RARα (PRα/LBD<sup>+</sup>) 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<sup>+</sup> (40%), 7 of whom (39%) relapsed Off-ATRA selection pressure, suggesting a possible active role of PRα/LBD<sup>+</sup>. Of 41 relapse patients coanalyzed, 15 (37%) had FMS-related tyrosine kinase 3 internal tandem duplication mutations (FLT3-ITD<sup>+</sup>), which were differentially associated with PRα/LBD<sup>+</sup> 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<sup>+</sup> were negatively associated and were oppositely associated with presenting white blood count and PML-RARα type: ACA, low, L-isoform; FLT3-ITD<sup>+</sup>, high, S-isoform. These exploratory results suggest that differing PRα/LBD<sup>+</sup> activities may interact with FLT3-ITD<sup>+</sup> or ACA, that FLT3-ITD<sup>+</sup> 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 <sup>+</sup> were also associated with reduced postrelapse survival. © 2012 by The American Society of Hematology.
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Gallagher, R. E., Moser, B. K., Racevskis, J., Poire, X., Bloomfield, C. D., Carroll, A. J., Ketterling, R. P., Roulston, D., Schachter-Tokarz, E., Zhou, D.-C., Chen, I.-M. L., Harvey, R., Koval, G., Sher, D. A., Feusner, J. H., Tallman, M. S., Larson, R. A., Powell, B. L., Appelbaum, F. R., et al. (2012). Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. Blood, 120(10), 2098-2108. https://doi.org/10.1182/blood-2012-01-407601 (Original work published 2012)