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. 2008 Apr 15;5(4):e83.
doi: 10.1371/journal.pmed.0050083.

In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile

Michael J Sorich  1 , Nicolas Pottier, Deqing Pei, Wenjian Yang, Leo Kager, Gabriele Stocco, Cheng Cheng, John C Panetta, Ching-Hon Pui, Mary V Relling, Meyling H Cheok, William E Evans
Affiliations

In vivo response to methotrexate forecasts outcome of acute lymphoblastic leukemia and has a distinct gene expression profile

Michael J Sorich (VSports在线直播) et al. PLoS Med. .

"VSports手机版" 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 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 VSports手机版. .

Methods and findings: 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 V体育安卓版. 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 V体育ios版. .

Trial registrations: Total XV, Therapy for Newly Diagnosed Patients With Acute Lymphoblastic Leukemia, http://www VSports最新版本. 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). .

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"VSports最新版本" Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. CONSORT Flow Chart Describing Patients Enrolled in Randomized Clinical Trials at St. Jude Children's Research Hospital, from Which the Current Study Population Was Derived
The flow chart includes study relevant protocol information for the St. Jude Children's Research Hospital Total Therapy Protocols XIIIA, XIIIB, and XV. Specifically, from the population that received ALL treatment according to one of these three protocols, the current study included only patients who received HDMTX as initial therapy. These protocols included a randomization to determine whether patients received HDMTX or not as initial treatment, the infusion time of HDMTX, and whether MP was given after MTX (LDMTX, low-dose methotrexate). Patients with an insufficient number of ALL cells for gene expression analysis were excluded, as were patients with insufficient data on circulating ALL cells to assess response over 3 d.
Figure 2
Figure 2. Scatterplot of WBCDay3 versus WBCPRE
This plot illustrates the leukemia cell count on day 3 (WBCDay3) after initial HDMTX treatment versus the pretreatment leukemia cell count (WBCPRE) at diagnosis in 293 patients. The solid line indicates the linear regression, and the dotted line the 95% confidence interval with p < 0.0001, r = 0.76, Spearman rank correlation, and p < 0.0001, r = 0.79, Pearson correlation.
Figure 3
Figure 3. Hierarchical Clustering of Genes Discriminating MTX Response (WBCΔDay3)
Hierarchical clustering using the top 50 most discriminant gene probe sets (Table S3) discriminating MTX response in 161 patients. Each column represents an ALL sample labeled with red circles for MTX poor responders (n = 40, top quartile of WBCΔDay3) and with green circles for MTX good responders (n = 40, bottom quartile of WBCΔDay3). Unlabeled patients are intermediate MTX responders. Each row represents a probe set labeled with the gene symbol. The “heat map” indicates high (red) or low (green) level of expression according to the scale shown.
Figure 4
Figure 4. Scatterplot of WBCΔDay3 Versus Level of Total MTXPGs
There is a significant correlation of WBCΔDay3 with the total MTXPG level in ALL cells from 230 patients (i.e., a higher total MTXPG concentration is associated with a better in vivo MTX response) (p = 0.0001, r = −0.25, Pearson correlation).
Figure 5
Figure 5. Kaplan-Meier Plots of Disease Relapse Categorized by WBCΔDay3, TYMS, and Top 50 Gene Profile
(A) MTX response is categorized by WBCΔDay3 MTX good responders (i.e., bottom quartile, n = 28), intermediate (n = 67), and poor (i.e., top quartile, n = 41) among 293 patients. (B) Top 50 gene expression profile is categorized by top 25% (gene profile for good responder, n = 20), intermediate (n = 53), and bottom 25% (gene profile for poor responder, n = 19). (C) Proliferation index is categorized by TYMS expression top 25% (high proliferation index, n = 27), intermediate (n = 47) and bottom 25% (low proliferation index, n = 18). For TYMS and top 50 gene profile, categorization was done among the 161 patients who had ALL cell gene expression data available.
Figure 6
Figure 6. Model Performance in an Independent Test Set of Patients
Relation between the in vivo MTX response (WBCΔDay3) and top 50 gene expression profile (p = 0.0065, r = 0.62, Pearson correlation) for the independent validation cohort (n = 18). Relation between (B) the predicted log(WBCDay3) using either the linear model function or (C) the median percentage drop determined in 293 patients (mean difference = 0.1812946. p = 0.0025, paired t-test). The regression lines in graphs (B) and (C) are based on intercept equal to zero and slope equal to one.
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