High Expression of Transcription Factor Yin Yang 1 and Multidrug Resistance Protein in Early B-Cell Precursors in Childhood Acute Lymphoblastic Leukemia.

Abstract 4695

Acute lymphoblastic leukemia (ALL) accounts for approximately 80% of acute leukemias during childhood, and is one of the leading causes of death for children with cancer. One of the main problems in treating ALL patients is the developing of drug resistance. Resistance to multiple anticancer drugs, so called multidrug resistance (MDR), most likely involves a nonspecific mechanism, through drug-efflux transporters. One of the most extensively studied proteins involved in MDR is the multidrug resistance protein 1 (MRP1), which up-regulates membrane-resident transporters that efflux chemotherapeutic drugs from tumor cells. YY1 is a ubiquitous and multifunctional transcription factor that can act as a transcriptional repressor, activator, or initiator element binding protein, depending on the context in which it binds. YY1 has been identified as a potential regulation factor for several genes involved in immuno and chemoresistance. We have previously reported that YY1 can act as transcription repressor for both Fas and TRAIL/DR5 (apoptosis pathways) in prostate and lymphoma cell lines. In addition to YY1-mediated regulation of tumor cell resistance to cytotoxic immunotherapy, it also has been shown to regulate resistance to chemotherapy. Several drugs used in prostate cancer therapy inhibit YY1 leading to any up-regulation of DR5. Using a TESS analysis we have found that the MRP1 promoter includes 4 binding sites for YY1. Hence, we hypothesized that one mechanism for ALL to become refractory to chemotherapy may be due to over-expression of YY1 and MRP1. This hypothesis was tested using immunohistochemistry of purified mononuclear cells from peripheral blood of 30 untreated ALL patients from the Children Hospital of Mexico Federico Gomez. (Mexico City). Immunostainings were performed to determine the expression of YY1 and MRP1, and both the frequency of positive cells and signal intensities were recorded. Our findings reveal that YY1 and MRP1 were over-expressed in the many of the ALL patient specimens comparing to normal controls (P=0.001), and there was a direct correlation between YY1 and MRP1 expression. In addition, we used flow cytometry to sort Pre-pro-B, Pre-B, Pro-B and B cell precursors from ALL patients before analyzing the YY1 and MRP1 expression by immunohistochemistry within each purified population. Our results demonstrated that YY1 and MRP1 were highly expressed in all the early stages of B cell development, suggesting that over-expression of YY1 and MRP1 may be involved in the pathogenesis of ALL. Furthermore, inhibitors of YY1 and MRP1 expression/activity might be targets for therapeutic intervention.