Catherine Leith, MB, Bchir

Associate Professor of Pathology and Laboratory Medicine

Member of the University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Tumor resistance to chemotherapy, either innate or acquired, is an important problem in the treatment of patients with malignancies. Over the last few years, I have been particularly interested in the problem of multidrug resistance in acute myeloid leukemia (AML). AML occurs predominantly of adults, increasing in frequency with advancing age (median age at presentation of about 62 years). Although most patients with AML achieve a complete remission (CR) with induction therapy, the majority will subsequently relapse and die of therapy resistant disease.

One possible drug resistance mechanism in AML is that mediated by the multidrug resistance gene, MDR1. This gene encodes the transmembrane protein, MDR1, also known as p-glycoprotein or p-gp, a member of the ATP-binding Cassette (ABC) protein superfamily. P-glycoprotein can extrude a variety of chemically and structurally unrelated substances out of the cell, including chemotherapeutic agents such as daunomycin, a key drug in AML therapy.

In collaboration with the Southwest Oncology Group (SWOG), I have evaluated the importance of MDR1 expression on clinical response to therapy in AML patients. We optimized assays to examine both MDR1 expression and functional efflux activity in primary leukemia samples from patients enrolled in SWOG protocols. Using these assays, I have examined MDR1 expression and functional activity in both elderly and younger patients diagnosed with AML and registered onto AML clinical trials. The group of elderly patients was of particular interest as these have a poor response to therapy, with overall survival of less than 10% at 2 years. Whether this poor response is due to highly resistant disease, or because older patients are not able to withstand the rigors of therapy was unclear.

I found that MDR1 expression frequency increased with patient ages, and was very commonly expressed in the elderly patient group. MDR1 expression and functional activity were both highly predictive of complete remission (CR) rate in this patient group. In addition, poor prognosis cytogenetics, and evidence of an antecedent myelodysplasia or prior chemotherapy were both highly predictive of outcome. Among the younger AML patients, frequency of MDR1 expression was lower, but again was an important predictor of CR rate.

During these studies, I also identified patients with novel MDR1-independent drug efflux mechanisms. Further characterization of these mechanisms is one research goal. I am also interested in identifying pathologic features that would be helpful either for the diagnosis or prognostic stratification of patients with hematopoietic malignancies. In this regard I have worked on a variety of projects including identification of hematogones in the bone marrow of ALL patients recovering from chemotherapy, and description of morphologic, phenotypic and genotypic features which may be useful in better classifying particular lymphomas/leukemias.

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