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Blood, Vol. 92 No. 4 (August 15), 1998:
pp. 1172-1183
Leukemic Cellular Retinoic Acid Resistance and Missense Mutations
in the PML-RAR Fusion Gene After Relapse of Acute Promyelocytic
Leukemia From Treatment With All-trans Retinoic Acid and
Intensive Chemotherapy
Wei Ding,
Yun-Ping Li,
Lucio M. Nobile,
George Grills,
Ines Carrera,
Elisabeth Paietta,
Martin S. Tallman,
Peter H. Wiernik, and
Robert E. Gallagher
From the Montefiore Medical Center and Albert Einstein Cancer Center,
Bronx, NY; the Northwestern University Medical School, Chicago, IL; and
the Eastern Cooperative Oncology Group, Brookline, MA.
This study evaluated whether relapse of acute promyelocytic leukemia
(APL) patients from clinical remissions achieved and/or maintained with all-trans retinoic acid (RA) in combination
with intensive chemotherapy is associated with leukemic cellular
resistance to RA and with alterations in the PML-RAR fusion gene. We
studied matched pretreatment and relapse specimens from 12 patients who received variable amounts of RA, primarily in nonconcurrent combination with daunorubicin and cytarabine (DA) on Eastern Cooperative Oncology Group (ECOG) protocol E2491, and from 8 patients who received DA only
on protocol E2491. Of 10 RA-treated patients evaluable for a change in
APL cell sensitivity to RA-induced differentiation in vitro, 8 showed
diminished sensitivity at relapse, whereas, of 6 evaluable patients
treated with DA alone, only 1 had marginally reduced sensitivity. From
analysis of sequences encoding the principal functional domains of the
PML and RAR portions of PML-RAR, we found missense mutations in
relapse specimens from 3 of 12 RA-treated patients and 0 of 8 DA-treated patients. All 3 mutations were located in the ligand binding
domain (LBD) of the RAR region of PML-RAR. Relative to normal
RAR1, the mutations were Leu290Val, Arg394Trp, and Met413Thr. All
pretreatment analyses were normal except for a C to T base change in
the 3 -untranslated (UT) region of 1 patient that was also
present after relapse from DA therapy. No mutations were detected in
the corresponding sequences of the normal RAR or PML (partial)
alleles. Minor additional PML-RAR isoforms encoding truncated PML
proteins were detected in 2 cases. We conclude that APL cellular
resistance occurs with high incidence after relapse from RA + DA
therapy administered in a nonconcurrent manner and that mutations in
the RAR region of the PML-RAR gene are present in and likely
mechanistically involved in RA resistance in a subset of these cases.
© 1998 by The American Society of Hematology.
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