Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia

Robert E. Gallagher, Barry K. Moser, Janis Racevskis, Xavier Poiré, Clara D. Bloomfield, Andrew J. Carroll, Rhett P. Ketterling, Diane Roulston, Esther Schachter-Tokarz, Da Cheng Zhou, I. Ming L Chen, Richard Harvey, Greg Koval, Dorie A. Sher, James H. Feusner, Martin S. Tallman, Richard A. Larson, Bayard L. Powell, Frederick R. Appelbaum, Elisabeth Paietta & 2 others Cheryl L. Willman, Wendy Stock

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)2098-2108
Number of pages11
JournalBlood
Volume120
Issue number10
DOIs
StatePublished - Sep 6 2012

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Acute Promyelocytic Leukemia
Chromosomes
Tretinoin
Chromosome Aberrations
Mutation
Recurrence
Therapeutics
Protein Isoforms
Chemotherapy
Protein-Tyrosine Kinases
Disease Progression
Blood
Clone Cells

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Gallagher, R. E., Moser, B. K., Racevskis, J., Poiré, X., Bloomfield, C. D., Carroll, A. J., ... Stock, W. (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

Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. / Gallagher, Robert E.; Moser, Barry K.; Racevskis, Janis; Poiré, Xavier; Bloomfield, Clara D.; Carroll, Andrew J.; Ketterling, Rhett P.; Roulston, Diane; Schachter-Tokarz, Esther; Zhou, Da Cheng; Chen, I. Ming L; Harvey, Richard; Koval, Greg; Sher, Dorie A.; Feusner, James H.; Tallman, Martin S.; Larson, Richard A.; Powell, Bayard L.; Appelbaum, Frederick R.; Paietta, Elisabeth; Willman, Cheryl L.; Stock, Wendy.

In: Blood, Vol. 120, No. 10, 06.09.2012, p. 2098-2108.

Research output: Contribution to journalArticle

Gallagher, RE, Moser, BK, Racevskis, J, Poiré, X, Bloomfield, CD, Carroll, AJ, Ketterling, RP, Roulston, D, Schachter-Tokarz, E, Zhou, DC, Chen, IML, Harvey, R, Koval, G, Sher, DA, Feusner, JH, Tallman, MS, Larson, RA, Powell, BL, Appelbaum, FR, Paietta, E, Willman, CL & Stock, W 2012, 'Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia', Blood, vol. 120, no. 10, pp. 2098-2108. https://doi.org/10.1182/blood-2012-01-407601
Gallagher, Robert E. ; Moser, Barry K. ; Racevskis, Janis ; Poiré, Xavier ; Bloomfield, Clara D. ; Carroll, Andrew J. ; Ketterling, Rhett P. ; Roulston, Diane ; Schachter-Tokarz, Esther ; Zhou, Da Cheng ; Chen, I. Ming L ; Harvey, Richard ; Koval, Greg ; Sher, Dorie A. ; Feusner, James H. ; Tallman, Martin S. ; Larson, Richard A. ; Powell, Bayard L. ; Appelbaum, Frederick R. ; Paietta, Elisabeth ; Willman, Cheryl L. ; Stock, Wendy. / Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia. In: Blood. 2012 ; Vol. 120, No. 10. pp. 2098-2108.
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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.",
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AU - Gallagher, Robert E.

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AU - Poiré, Xavier

AU - Bloomfield, Clara D.

AU - Carroll, Andrew J.

AU - Ketterling, Rhett P.

AU - Roulston, Diane

AU - Schachter-Tokarz, Esther

AU - Zhou, Da Cheng

AU - Chen, I. Ming L

AU - Harvey, Richard

AU - Koval, Greg

AU - Sher, Dorie A.

AU - Feusner, James H.

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AU - Larson, Richard A.

AU - Powell, Bayard L.

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N2 - 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.

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