A pathway-based gene signature correlates with therapeutic response in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

Abstract

Biomarkers to predict response to therapy in adults with Philadelphia chromosome-positive (Ph þ ) acute lymphoblastic leukemia (ALL) are not yet established. In this study, we performed a meta-analysis of earlier genome-wide gene expression studies to identify pathway-based genes that are associated with therapeutic response. The predictive power of these genes was validated by transcript profiling in diagnostic bone marrow samples from Ph þ ALL patients using a quantitative real-time PCR array. Gene expression was correlated with cytogenetic and molecular characteristics, including presence of ABL1 mutations and IKZF1 deletion. A total of 43 de novo Ph þ ALL patients treated uniformly with tyrosine kinase inhibitors combined with chemotherapy were selected to validate 46 identified genes. A 9-gene signature was established to distinguish optimal responders from patients with persistent residual disease and early molecular recurrence. The signature was subsequently validated with 87% predictive accuracy in an independent validation set of patients. When initially optimal responders relapsed, their gene expression patterns also shifted. Optimal responders showed upregulation of genes involved in proliferation and apoptosis pathways, whereas poor responders had higher expression of genes that facilitate tumor cell survival in hypoxic conditions as well as development of drug resistance. This unique 9-gene signature may better enable stratification of patients to proper therapeutic regimens and provides new insights into mechanisms of Ph þ ALL response to therapy.

High frequency of IKZF1 genetic alterations in adult patients with B‐cell acute lymphoblastic leukemia

“…However, the same has not been achieved in the case of adult B‐ALL. Philadelphia chromosome–positive ALL (Ph + ALL) accounts for approximately one‐third of adult B‐ALL cases , whereas cytogenetic alterations that serve as predictors of favorable prognosis in pediatric B‐ALL, such as t(12,21)(p13;q22) and high hyperdiploidy, are less frequent in adult patients with B‐ALL . Therefore, cytogenetic differences are likely to explain the difference in therapeutic outcome between adult and pediatric ALL.…”

Early Risk Prediction of BCR-ABL Kinase Domain Acquired Mutations in Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

“…MRD monitoring and BCR/ABL KD mutation are irreplaceable for the successful management of Ph + ALL patients [2] . Nevertheless, 30% of the patients treated with imatinib relapse in a short time interval [13] and there are still some obstructions that remain to be settled on the way to therapy optimization.…”

The Role of miRNAs in Childhood Acute Lymphoblastic Leukemia Relapse and the Associated Molecular Mechanisms

“…Finally, regarding the gene expression patterns in ALL, Philadelphia chromosome-positive (Ph+) ALL was correlated with the presence of ABL1 mutations and IKZF1 deletion. Among the BCR/ABL-like genes, the correlated genes were IGH@CRLF2, NUP214-ABL1, EBF1-PDGFRB, BCRJAK2, STRN3-JAK2, IGH@-EPOR, ∆-CRLF2 and IKZF1 deletion [ 25 ]. In ALL with TCR translocations and various oncogenes t(1;14) t(10;14) t(5;14), the genes involved are LMO1, LMO2, TAL1, TLX1, and TLX3, while in the Del(1)(p32) translocation, SIL-TAL1 is the gene involved.…”