Multidrug resistance protein expression in chronic myeloid leukemia: associations and significance.
BACKGROUND
Overexpression of the multidrug resistance gene (MDR1) product, the MDR1 protein (MDR1), has been associated with poor prognosis in several hematologic malignancies. The significance of MDR1 levels in patients with chronic myeloid leukemia (CML) has not been established.


METHODS
The authors investigated MDR1 levels and their association with patient and tumor characteristics, responsiveness to therapy, and long term prognosis in 198 CML patients. These included 127 patients in early chronic phase (ECP) CML, 31 patients in late chronic phase (LCP) CML, and 40 patients in accelerated or blastic phase CML. MDR1 expression was analyzed by Western blot analysis and quantitative solid-phase plate radioimmunoassay. MDR1 levels were measured on cell lysates obtained from the bone marrow mononuclear cell fraction. Expression was compared in relation to the median derived from 36 normal control samples.


RESULTS
Among patients with CML, high levels of MDR1 were found in 73 of 127 ECP (57%), 20 of 31 LCP (65%), 8 of 27 in accelerated phase (30%), and 8 of 13 in blastic phase (62%) (P value not significant). Furthermore, among the 127 ECP CML patients, high MDR1 levels were associated with age >/=50 years (69% vs. 51%; P < 0. 05), thrombocytosis >700 x 10(9)/L (84% vs. 53%; P < 0.01), and leukocyte counts </=50 x 10(9)/L (70% vs. 46%; P < 0.01). Response to interferon alpha (IFN-alpha) was independent of MDR1 expression; major cytogenetic responses were recorded in 28 of 73 patients with high MDR1 levels and in 16 of 54 patients with low MDR1 levels (38% vs. 30%; P value not significant). No difference in survival based on MDR1 level was observed. A small subset of 17 patients with low MDR1 levels (<1 times normal) had a trend toward worse survival (median, 30 months vs. 73 months; 5-year survival rates of 34% vs. 65%; P = 0.03).


CONCLUSIONS
The results of the current study demonstrate that MDR1 overexpression was not associated with disease progression, responsiveness to IFN-alpha therapy, or survival in patients with ECP CML.
Giles
F J
FJ
Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, Texas, USA.
Kantarjian
H M
HM
Cortes
J
J
Thomas
D A
DA
Talpaz
M
M
Manshouri
T
T
Albitar
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000096:biosynthesis* / Q000302:isolation & purification; D000970:Antineoplastic Agents / Q000627:therapeutic use; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D015151:Immunoblotting; D016898:Interferon-alpha / Q000627:therapeutic use; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011379:Prognosis; D011863:Radioimmunoassay; D016019:Survival Analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D016898:Interferon-alpha