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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.

C. Leith, K. Kopecky, I. Chen, L. Eijdems, M. Slovak, T. McConnell, D. Head, J. Weick, M. Grever, F. Appelbaum, C. Willman
Published 1999 · Biology, Medicine

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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 (P(MDR1) =.012; P(efflux) =.039) and resistant disease (RD; P(MDR1) =.0007; P(efflux) =.0092). No such correlations were observed for MRP1 (P(CR) =.93; P(RD) =.55) or LRP (P(CR) =.50; P(RD) =.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.
This paper references
10.1007/978-1-4612-4380-9_25
Nonparametric Estimation from Incomplete Observations
E. Kaplan (1958)
10.2307/2344247
The analysis of binary data
D. Cox (1970)
Regression models and life tables (with discussion
D. Cox (1972)
10.1080/00224065.1986.11978989
Applied Linear Statistical Models
M. Kutner (1974)
10.1177/25.7.894009
Proof without prejudice: use of the Kolmogorov-Smirnov test for the analysis of histograms from flow systems and other sources.
I. T. Young (1977)
10.32388/78qroa
An international system for human cytogenetic nomenclature
Iscn (1978)
10.1016/S0165-4608(84)80022-9
Clinical significance of chromosomal abnormalities in acute lymphoblastic leukemia.
C. Bloomfield (1981)
10.1002/1097-0142(19850501)55:9<1979::AID-CNCR2820550925>3.0.CO;2-#
Institutional performance in application of the FAB classification of acute leukemia. The southwest oncology group experience
D. Head (1985)
10.1016/S0140-6736(86)92674-7
PRINCIPAL RESULTS OF THE MEDICAL RESEARCH COUNCIL'S 8th ACUTE MYELOID LEUKAEMIA TRIAL
J. Rees (1986)
10.1182/BLOOD.V69.6.1551.BLOODJOURNAL6961551
Acute myelogenous leukemia: recent advances in therapy
R. Champlin (1987)
10.1016/0145-2126(87)90017-8
Toward a clinically relevant cytogenetic classification of acute myelogenous leukemia.
M. Keating (1987)
10.1111/j.1365-2141.1988.tb06188.x
Refined chromosome study helps define prognostic subgroups in most patients with primary myelodysplastic syndrome and acute myelogenous leukaemia
J. Yunis (1988)
10.1182/BLOOD.V73.1.263.263
Prognostic impact of cytogenetic abnormalities in patients with de novo acute nonlymphocytic leukemia.
C. Schiffer (1989)
10.1016/0165-4608(89)90025-3
The clinical significance of karyotype in acute myelogenous leukemia.
D. Arthur (1989)
10.1111/j.1365-2141.1989.tb00221.x
Cytogenetics and their prognostic value in de novo acute myeloid leukaemia: a report on 283 cases
P. Fenaux (1989)
10.1111/j.1365-2141.1991.tb07947.x
High risk of early resistant relapse for leukaemic patients with presence of multidrug resistance associated P‐glycoprotein positive cells in complete remission
P. Musto (1991)
10.1093/JNCI/83.10.708
MDR1 gene expression and treatment outcome in acute myeloid leukemia.
R. Pirker (1991)
10.1126/SCIENCE.1360704
Overexpression of a transporter gene in a multidrug-resistant human lung cancer cell line.
S. Cole (1992)
10.1182/BLOOD.V79.2.473.BLOODJOURNAL792473
Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis.
L. Campos (1992)
10.1200/JCO.1993.11.9.1652
Phase I/II trial of cyclosporine as a chemotherapy-resistance modifier in acute leukemia.
A. List (1993)
A Southwest Oncology Group study
T. Jenkins (1993)
Cyclosporin A as a modifier agent in the salvage treatment of acute leukemia (AL).
J. Marie (1993)
The MRP gene associated with a non-P-glycoprotein multidrug resistance encodes a 190-kDa membrane bound glycoprotein.
N. Krishnamachary (1993)
10.1111/j.1365-2141.1994.tb08305.x
P‐glycoprotein expression on acute myeloid leukaemia blast cells at diagnosis predicts response to chemotherapy and survival
P. Wood (1994)
Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias.
H. Burger (1994)
Expression of the multidrug resistance-associated protein (MRP) in acute leukaemia.
S. Hart (1994)
Significantly lower P-glycoprotein expression in acute promyelocytic leukemia than in other types of acute myeloid leukemia: immunological, molecular and functional analyses.
E. Paietta (1994)
10.1016/0006-2952(94)90538-X
Analysis of MRP mRNA in mitoxantrone-selected, multidrug-resistant human tumor cells.
B. Futscher (1994)
10.1006/GENO.1994.1237
Cloning of two novel ABC transporters mapping on human chromosome 9.
M. Luciani (1994)
P-glycoprotein expression as unfavorable prognostic factor in acute myeloid leukemia.
S. Zoechbauer (1994)
10.1073/PNAS.91.19.8822
The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump.
G. Zaman (1994)
10.1073/PNAS.91.26.13033
Overexpression of the gene encoding the multidrug resistance-associated protein results in increased ATP-dependent glutathione S-conjugate transport.
M. Müller (1994)
10.1182/BLOOD.V86.5.1717.BLOODJOURNAL8651717
Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia.
D. Head (1995)
Expression of the multidrug resistance-associated protein (MRP) gene in human cancers.
K. Nooter (1995)
10.1038/bjc.1995.371
Functional detection of MDR1/P170 and MRP/P190-mediated multidrug resistance in tumour cells by flow cytometry.
N. Feller (1995)
Functional multidrug resistance phenotype associated with combined overexpression of Pgp/MDR1 and MRP together with 1-beta-D-arabinofuranosylcytosine sensitivity may predict clinical response in acute myeloid leukemia.
G. Schuurhuis (1995)
10.1038/nm0695-578
The drug resistance-related protein LRP is the human major vault protein
G. Scheffer (1995)
Expression of multidrug resistance-associated protein (MRP) and multidrug resistance (MDR1) genes in acute myeloid leukemia.
D. Zhou (1995)
10.1073/PNAS.92.17.7690
Role of glutathione in the export of compounds from cells by the multidrug-resistance-associated protein.
G. Zaman (1995)
10.1182/BLOOD.V85.8.2147.BLOODJOURNAL8582147
Predictive value for treatment outcome in acute myeloid leukemia of cellular daunorubicin accumulation and P-glycoprotein expression simultaneously determined by flow cytometry.
A. Guerci (1995)
10.1182/BLOOD.V85.1.186.BLOODJOURNAL851186
Increased expression of the multidrug resistance-associated protein gene in relapsed acute leukemia.
E. Schneider (1995)
10.1002/1097-0142(19950201)75:3<815::AID-CNCR2820750311>3.0.CO;2-R
A phase III randomized study of oral verapamil as a chemosensitizer to reverse drug resistance in patients with refractory myeloma. A southwest oncology group study
William S. Dalton (1995)
10.1182/BLOOD.V86.6.2329.BLOODJOURNAL8662329
Correlation of multidrug resistance (MDR1) protein expression with functional dye/drug efflux in acute myeloid leukemia by multiparameter flow cytometry: identification of discordant MDR-/efflux+ and MDR1+/efflux- cases.
C. Leith (1995)
Multi-drug resistance (MDR) activity in acute leukemia determined by rhodamine 123 efflux assay.
T. Lamy (1995)
10.1002/(SICI)1097-0320(19960901)25:1<14::AID-CYTO2>3.0.CO;2-E
DiOC2(3) is not a substrate for multidrug resistance protein (MRP)-mediated drug efflux.
H. Minderman (1996)
Methods to detect P-glycoprotein-associated multidrug resistance in patients' tumors: consensus recommendations.
W. Beck (1996)
10.1182/BLOOD.V87.6.2464.BLOODJOURNAL8762464
Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia.
A. List (1996)
10.1182/BLOOD.V88.8.2841.BLOODJOURNAL8882841
A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: a Southwest Oncology Group study.
J. Weick (1996)
Expression of multidrug resistance-associated protein (MRP) mRNA in blast cells from acute myeloid leukemia (AML) patients.
D. Ross (1996)
10.1016/0959-8049(96)00046-9
Biology of the multidrug resistance-associated protein, MRP.
D. Loe (1996)
10.1182/BLOOD.V89.9.3323
Acute myeloid leukemia in the elderly: assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkably distinct responses to standard chemotherapy. A Southwest Oncology Group study.
C. Leith (1997)
10.1002/(SICI)1097-0320(19971015)30:5<236::AID-CYTO4>3.0.CO;2-F
U.S.-Canadian Consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: data analysis and interpretation.
M. Borowitz (1997)
10.1046/j.1365-2141.1997.d01-2020.x
P‐glycoprotein (PGP) and lung resistance‐related protein (LRP) expression and function in leukaemic blast cells
M. Michieli (1997)
Multidrug resistance-associated protein in acute myeloid leukemia: No impact on treatment outcome.
M. Filipits (1997)
10.1002/(SICI)1097-0320(19971015)30:5<249::AID-CYTO6>3.0.CO;2-C
U.S.-Canadian Consensus recommendations on the immunophenotypic analysis of hematologic neoplasia by flow cytometry: medical indications.
B. Davis (1997)
10.1006/GENO.1996.4500
The cloning of a human ABC gene (ABC3) mapping to chromosome 16p13.3.
T. Connors (1997)
10.1073/PNAS.95.26.15665
A multidrug resistance transporter from human MCF-7 breast cancer cells.
L. Doyle (1998)
10.1021/BI9718043
Kinetic analysis of calcein and calcein-acetoxymethylester efflux mediated by the multidrug resistance protein and P-glycoprotein.
M. Essodaigui (1998)
10.1182/BLOOD.V91.5.1508.1508_1508_1513
Expression of the Lung Resistance Protein Predicts Poor Outcome in De Novo Acute Myeloid Leukemia
M. Filipits (1998)
10.1038/sj.leu.2401117
Lung resistance protein (LRP) gene expression in adult acute myeloid leukemia: a critical evaluation by three techniques
O. Legrand (1998)
10.1182/BLOOD.V91.12.4480.412K28_4480_4488
Pgp and MRP activities using calcein-AM are prognostic factors in adult acute myeloid leukemia patients
O. Legrand (1998)



This paper is referenced by
10.1016/j.drup.2020.100742
Taxanes in cancer treatment: Activity, chemoresistance and its overcoming.
L. Mosca (2021)
10.1007/978-3-030-72676-8_7
Prognostic Factors in AML
R. Itzykson (2021)
10.3390/ijms21165626
Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment
L. Fenwarth (2020)
10.1007/s12094-020-02383-x
Comparison of efficacy of HCAG and CAG re-induction chemotherapy in elderly low- and intermediate-risk group patients diagnosed with acute myeloid leukemia
J. Zhang (2020)
10.1182/bloodadvances.2019001188
A novel C2 domain binding CD33xCD3 bispecific antibody with potent T-cell redirection activity against acute myeloid leukemia.
Priyanka Nair-Gupta (2020)
10.1182/bloodadvances.2020001576
Clinical MDR1 inhibitors enhance Smac-mimetic bioavailability to kill murine LSCs and improve survival in AML models.
Emma Morrish (2020)
10.1007/s00277-020-03922-w
Post-remission therapy of adults aged 60 and older with acute myeloid leukemia in first complete remission: role of treatment intensity on the outcome
B. Bouchacourt (2020)
10.1007/978-3-030-53633-6_3
Insights into the Pathobiology of Secondary AML
T. Jain (2020)
10.2174/1568026619666190305130141
How Cancer Cells Resist Chemotherapy: Design and Development of Drugs Targeting Protein-Protein Interactions.
V. Tarasov (2019)
10.1016/j.jconrel.2019.01.011
Combinatorial nanocarriers against drug resistance in hematological cancers: Opportunities and emerging strategies
Saikat Ghosh (2019)
10.1186/s12935-019-0815-0
The role of photodynamic therapy on multidrug resistant breast cancer
E. C. Aniogo (2019)
10.1016/j.drudis.2019.09.017
Clinical applications of nanomedicine in cancer therapy.
M. Norouzi (2019)
10.3390/ijms20174095
Chk1 Inhibitor MK-8776 Restores the Sensitivity of Chemotherapeutics in P-glycoprotein Overexpressing Cancer Cells
Qingbin Cui (2019)
10.3324/haematol.2018.208637
Comparisons of commonly used front-line regimens on survival outcomes in patients aged 70 years and older with acute myeloid leukemia
Chetasi Talati (2019)
10.4274/tjh.galenos.2019.2018.0220
Comparison of Myeloablative Versus Reduced-Intensity Conditioning Regimens for Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia: A Cohort Study
R. Çiftçiler (2019)
10.1007/s00277-019-03606-0
The leukemia strikes back: a review of pathogenesis and treatment of secondary AML
E. Cheung (2019)
10.3389/fphar.2019.00481
CYP2J2∗7 Genotype Predicts Risk of Chemotherapy-Induced Hematologic Toxicity and Reduced Relative Dose Intensity in Ethiopian Breast Cancer Patients
Jemal Hussien Ahmed (2019)
10.31557/APJCP.2019.20.8.2421
Chemotherapeutic Resistance in Egyptian Acute Myeloid Leukemia Patients
Neemat M. Kassem (2019)
10.1111/bjh.16359
Twenty five years of UK trials in acute myeloid leukaemia: what have we learned?
A. Burnett (2019)
10.1007/164_2017_20
Molecular and Pharmacological Mechanisms of Drug Resistance:An Evolving Paradigm.
B. Colmegna (2018)
10.1182/blood-2017-08-802157
No evidence that CD33 splicing SNP impacts the response to GO in younger adults with AML treated on UK MRC/NCRI trials.
R. Gale (2018)
10.1038/s41551-018-0310-2
Conjugation of haematopoietic stem cells and platelets decorated with anti-PD-1 antibodies augments anti-leukaemia efficacy
Q. Hu (2018)
10.18632/oncotarget.24930
Establishment of preclinical chemotherapy models for gastroenteropancreatic neuroendocrine carcinoma
A. Ohmoto (2018)
10.1158/1535-7163.MCT-17-1077
IMGN779, a Novel CD33-Targeting Antibody–Drug Conjugate with DNA-Alkylating Activity, Exhibits Potent Antitumor Activity in Models of AML
Yelena V. Kovtun (2018)
10.3390/cancers10060179
Allogeneic Hematopoietic Cell Transplantation for Older Adults with Acute Myeloid Leukemia
J. J. Lipof (2018)
10.1039/c7md00178a
Tetrahydroquinolinone derivatives as potent P-glycoprotein inhibitors: design, synthesis, biological evaluation and molecular docking analysis.
S. Ranjbar (2017)
10.1111/ejh.12913
BCRP mRNA and FLT3‐ITD are independent poor risk factors in adult patients with acute myeloid leukemia and intermediate or normal karyotype
B. Nasiłowska-Adamska (2017)
10.1016/j.drup.2017.10.003
Not only P-glycoprotein: Amplification of the ABCB1-containing chromosome region 7q21 confers multidrug resistance upon cancer cells by coordinated overexpression of an assortment of resistance-related proteins.
Ilaria Genovese (2017)
10.1038/bmt.2016.251
Inhibition of FLT3 in AML: a focus on sorafenib
A. Antar (2017)
10.1016/j.jgo.2017.08.004
Emerging therapeutic modalities for acute myeloid leukemia (AML) in older adults.
Li-wen Huang (2017)
Treatment of acute lymphoblastic leukemia in older adults: now and the future.
M. Yilmaz (2017)
10.1016/j.leukres.2017.09.014
Transfer of multidrug resistance among acute myeloid leukemia cells via extracellular vesicles and their microRNA cargo.
Céline Bouvy (2017)
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