MDR-1, but notMDR-3gene expression, is associated with unmutated IgV_Hgenes and poor prognosis chromosomal aberrations in chronic lymphocytic leukemia

Abstract

Two P-glycoprotein (P-gp) genes, MDR-1 (ABCB1) and MDR-3 (ABCB4), have been identified in humans. This study was designed to investigate whether associations exist between expression of MDR-1 and MDR-3 P-gp and other markers of poor prognosis and/or prior exposure to therapeutic agents in chronic lymphocytic leukemia (CLL). IgVH mutational status, gene usage, CD38 positivity, FISH analysis and clinical information were available on all patients. Twenty-one of 101 patients tested showed MDR-3 P-gp positivity. Associations with markers of poor prognosis or prior chemotherapy did not reach statistical significance, but MDR-3 P-gp positive patients had significantly shorter survivals than MDR-3 P-gp negative patients. MDR-1 P-gp expression (18/25) showed a strong association with unmutated IgVH genes and adverse prognosis cytogenetics (p = 0.015, p = 0.014, respectively), but was independent of prior exposure to chemotherapeutic agents. These results suggest a role for MDR-1 and MDR-3 in chemoresistant disease. This study highlights the value of determining MDR phenotype in CLL patients prior to treatment, to allow the design of novel drug regimens containing agents that reverse MDR function.

Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia

“…A new member of the ABC superfamily, ABCB4 possesses 80% homology to ABCB1. It is suggested that ABCB4 plays a supplementary role to ABCB1 in chronic lymphocytic leukemia (CLL) drug resistance (3) and might have an independent role in MDR in chronic lymphoproliferative disorders (CLPDs) (4,5). To date, however, ABCB4 expression has rarely been studied in AML.…”

Expression of multidrug resistance-associated ABC transporters in B-CLL is independent of ZAP70 status

“…When compared with other PB hematopoietic lineages and CD34-positive precursor cells; there was an expression proWle in normal and CLL B cells that was characterized by positivity for MDR1, MDR2, MRP1, MRP4, MRP5, and MRP7. MDR1 expression has previously been correlated to unmutated IgV H gene status and a poor prognosis in CLL (Matthews et al 2006). This observation was, however, not conWrmed in a cell population positive for ZAP70 (Guillaume et al 2007), which is a surrogate marker for unmutated IgV H status (Crespo et al 2003).…”

“…Both genes are overexpressed in CLL, and MDR1 has been associated with advanced clinical stages Sonneveld et al 1992). Furthermore, a correlation of MDR1 and MDR2 expression with unfavorable IgV H status and cytogenetic aberrations has been described (Matthews et al 2006). …”

Translocation of Nucleoside Analogs Across the Plasma Membrane in Hematologic Malignancies

“…[89] Concerning MDR3, a correlation of this protein and shorter survival has been described in CLL patients. [90] It has also been reported that MDR3 positivity may be associated with a more malignant phenotype in CLL, although this pattern was not observed with MDR1 positivity. [91] …”