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Supplementary Information

In vivo Response to Methotrexate forecasts Outcome of Acute Lymphoblastic Leukemia and has a Distinct Gene Expression Profile

Michael J. Sorich, Nicolas Pottier, Deqing Pei, Wenjian Yang, Leo Kager,Cheng Cheng, John C. Panetta, Ching-Hon Pui, Mary V. Relling, Meyling H. Cheok, William E. Evans

PLoS Med. 2008 Apr 15;5(4):e83.

Abstract

Background: Childhood acute lymphoblastic leukemia (ALL) is the most common cancer in children, and can now be cured in approximately 80% of patients. Nevertheless, drug resistance is the major cause of treatment failure in children with ALL. The drug methotrexate (MTX), which is widely used to treat many human cancers, is used in essentially all treatment protocols worldwide for newly diagnosed ALL. Although MTX has been extensively studied for many years, relatively little is known about mechanisms of de novo resistance in primary cancer cells, including leukemia cells. This is due in part to the fact that existing in vitro methods are not sufficiently reliable to permit assessment of MTX resistance in primary ALL cells. Therefore, a more complete understanding of the mechanisms of MTX resistance in ALL cells is needed if new treatment strategies are to be developed for patients whose leukemia is resistant to this important component of ALL chemotherapy.

Methods and Findings: We therefore utilized the reduction of circulating leukemia cells of 293 newly diagnosed children after initial “up-front” single-agent in vivo MTX treatment (1g/m2) to elucidate inter-patient differences in MTX’s antileukemic effects. To identify genomic determinants of MTX’s antileukemic effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed patients. We identified 48 genes and two cDNA clones whose expression was significantly related to the reduction of circulating leukemia cells after initial in vivo treatment with MTX. This finding was validated in an independent cohort of patients. Furthermore, this measure of initial MTX in vivo response and the associated gene expression pattern were predictive of long-term disease-free survival (p <0.001, p= 0.02).

Conclusions: Together, these data provide new insights into the genomic basis of MTX resistance and inter-patient differences in MTX response, pointing to new strategies to overcome MTX resistance

Data Files
cel.zip 507MB HTTP FTP
chp.zip 846MB HTTP FTP
geo161GE.all.txt 41MB HTTP FTP
key.txt 12KB HTTP FTP