In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile.
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 lack of knowledge 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, we measured the in vivo antileukemic effects of MTX and identified genes whose expression differed significantly in patients with a good versus poor response to MTX.


RESULTS
We utilized measures of decreased circulating leukemia cells of 293 newly diagnosed children after initial "up-front" in vivo MTX treatment (1 g/m(2)) to elucidate interpatient differences in the antileukemic effects of MTX. To identify genomic determinants of these effects, we performed a genome-wide assessment of gene expression in primary ALL cells from 161 of these newly diagnosed children (1-18 y). 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 children with ALL. 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 interpatient differences in MTX response, pointing to new strategies to overcome MTX resistance in childhood ALL.


BACKGROUND
Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www.ClinicalTrials.gov (NCT00137111); Total XIIIBH, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Intermediate or High Risk of Treatment Failure (NCI-T93-0101D); Total XIIIBL, Phase III Randomized Study of Antimetabolite-Based Induction plus High-Dose MTX Consolidation for Newly Diagnosed Pediatric Acute Lymphocytic Leukemia at Lower Risk of Treatment Failure (NCI-T93-0103D).
Sorich
Michael J
MJ
Hematological Malignancies Program and the Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, United States of America.
Pottier
Nicolas
N
Pei
Deqing
D
Yang
Wenjian
W
Kager
Leo
L
Stocco
Gabriele
G
Cheng
Cheng
C
Panetta
John C
JC
Pui
Ching-Hon
CH
Relling
Mary V
MV
Cheok
Meyling H
MH
Evans
William E
WE
D000293:Adolescent; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000627:therapeutic use*; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate / Q000008:administration & dosage / Q000627:therapeutic use*; D009360:Neoplastic Cells, Circulating; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016896:Treatment Outcome
D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate