The Early Treatment Response of the Clinically Challenging Group of Childhood T-ALL without NOTCH1 Mutations Is Signified by a Specific mRNA Gene Profile.
2007
Activating mutations within the NOTCH1 gene occur in more than 50% of childhood precursor T-cell lymphoblastic leukemia (T-ALL, Weng et al. Science 2004). Our previous work has shown that in the context of the ALL-BFM 2000 treatment strategy, activating NOTCH1 mutations significantly correlate with a good early treatment response and specified a subgroup of patients with an exceptionally favorable long term outcome. By contrast, most of the relapses occurred in those patients without NOTCH1 mutations, which thus represents a clinically important and challenging subgroup (Breit et al., Blood 2006). We now aimed to further differentiate this subgroup without NOTCH1 mutations by analyzing the mRNA expression profile of primary pediatric T-ALL bone marrow samples. We first validated the biological significance of these analyses by comparing samples with and without activating NOTCH1 mutations and confirmed that the presence of activating NOTCH1 mutations correlates with differential expression of multiple downstream signaling pathways that are known to be activated by NOTCH1. Importantly, the comparison of patients without NOTCH1 mutations and good or poor prednisolone response revealed a specific gene signature that differentiates wild-type NOTCH1 T-ALL with a favourable from those with an unfavourable early treatment response. These discriminatory signatures significantly enrich for specific gene ontology categories (e.g. cell death, cellular growth and proliferation, and molecular transport), suggesting functional relevance of these differentially expressed genes. The specific comparison of different T-ALL subgroups thus reveals prognostic gene expression signatures particularly in the clinically difficult patients without NOTCH1 mutations.
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