Treatment-influenced associations of PML-RARα mutations, FLT3 mutations, and additional chromosome abnormalities in relapsed acute promyelocytic leukemia.
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.
Albert Einstein College of Medicine, Bronx, NY 10467, USA. robert.gallagher@einstein.yu.edu
Robert E
RE
Gallagher
Barry K
BK
Moser
Janis
J
Racevskis
Xavier
X
Poiré
Clara D
CD
Bloomfield
Andrew J
AJ
Carroll
Rhett P
RP
Ketterling
Diane
D
Roulston
Esther
E
Schachter-Tokarz
Da-Cheng
DC
Zhou
I-Ming L
IM
Chen
Richard
R
Harvey
Greg
G
Koval
Dorie A
DA
Sher
James H
JH
Feusner
Martin S
MS
Tallman
Richard A
RA
Larson
Bayard L
BL
Powell
Frederick R
FR
Appelbaum
Elisabeth
E
Paietta
Cheryl L
CL
Willman
Wendy
W
Stock
D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002648:Child; D002675:Child, Preschool; D002869:Chromosome Aberrations; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007223:Infant; D007621:Karyotyping; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000401:mortality; D008875:Middle Aged; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D012008:Recurrence; D016019:Survival Analysis; D014212:Tretinoin / Q000008:administration & dosage* / Q000009:adverse effects; D051941:fms-Like Tyrosine Kinase 3 / Q000235:genetics*
D000970:Antineoplastic Agents; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3