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Blood, Vol. 94 No. 3 (August 1), 1999:
pp. 1086-1099
Frequency and Clinical Significance of the Expression of the
Multidrug Resistance Proteins MDR1/P-Glycoprotein, MRP1, and LRP in
Acute Myeloid Leukemia. A Southwest Oncology Group Study
Catherine P. Leith,
Kenneth J. Kopecky,
I-Ming Chen,
Lisette Eijdems,
Marilyn L. Slovak,
Thomas S. McConnell,
David R. Head,
James Weick,
Michael R. Grever,
Frederick R. Appelbaum, and
Cheryl L. Willman
From the Departments of Pathology and the Cancer Center,
University of New Mexico School of Medicine, Albuquerque, NM; the Fred
Hutchinson Cancer Research Center and the Department of Medicine,
University of Washington, and the Southwest Oncology Group (SWOG)
Statistical Center, Seattle, WA; the Cleveland Clinic, Florida
Division; the Department of Pathology, City of Hope Cancer
Center Program, Duarte, CA; the Department of Pathology, St Jude
Children's Hospital, Memphis, TN; and the Southwest Oncology Group
Leukemia and Cytogenetics Programs, San Antonio, TX.
Therapeutic resistance is a major obstacle in the treatment of acute
myeloid leukemia (AML). Such resistance has been associated with rapid
drug efflux mediated by the multidrug resistance gene 1 (MDR1; encoding
P-glycoprotein) and more recently with expression of other novel
proteins conferring multidrug resistance such as MRP1 (multidrug
resistance-associated protein 1) and LRP (lung resistance protein). To
determine the frequency and clinical significance of MDR1, MRP1, and
LRP in younger AML patients, we developed multiparameter flow
cytometric assays to quantify expression of these proteins in
pretreatment leukemic blasts from 352 newly diagnosed AML patients (median age, 44 years) registered to a single clinical trial (SWOG 8600). Protein expression was further correlated with functional efflux
by leukemic blasts [assessed using two substrates: Di(OC)2 and Rhodamine 123] and with the ability of MDR-reversing agents to
inhibit efflux in vitro. MDR1/P-glycoprotein expression, which was
highly correlated with cyclosporine-inhibited efflux, was noted in only
35% of these younger AML patients, distinctly lower than the frequency
of 71% we previously reported in AML in the elderly (Blood
89:3323, 1997). Interestingly, MDR1 expression and functional drug
efflux increased with patient age, from a frequency of only 17% in
patients less than 35 years old to 39% in patients aged 50 years
(P = .010). In contrast, MRP1 was expressed in only 10% of
cases and decreased with patient age (P = .024). LRP was
detected in 43% of cases and increased significantly with increasing
white blood cell counts (P = .0015). LRP was
also marginally associated with favorable cytogenetics (P = .012) and French-American-British (FAB) AML FAB subtypes (P = .013), being particularly frequent in M4/M5 cases. Only
MDR1/P-glycoprotein expression and cyclosporine-inhibited efflux were
significantly associated with complete remission (CR) rate
(PMDR1 = .012; Pefflux = .039) and resistant disease (RD; PMDR1
= .0007; Pefflux = .0092). No such correlations
were observed for MRP1 (PCR = .93;
PRD = .55) or LRP (PCR = .50; PRD = .53). None of these parameters were
associated with overall or relapse-free survival. Unexpectedly, a
distinct and nonoverlapping phenotype was detected in 18% of these
cases: cyclosporine-resistant efflux not associated with MDR1, MRP1, or
LRP expression, implying the existence of other as yet undefined efflux
mechanisms in AML. In summary, MDR1 is less frequent in younger AML
patients, which may in part explain their better response to therapy.
Neither MRP1 nor LRP are significant predictors of outcome in this
patient group. Thus, inclusion of MDR1-modulators alone may benefit
younger AML patients with MDR1(+) disease.
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