Clinical and molecular characterization of early T-cell precursor leukemia: a high-risk subgroup in adult T-ALL with a high frequency of FLT3 mutations

Abstract

A subgroup of pediatric acute T-lymphoblastic leukemia (T-ALL) was characterized by a gene expression profile comparable to that of early T-cell precursors (ETPs) with a highly unfavorable outcome. We have investigated clinical and molecular characteristics of the ETP-ALL subgroup in adult T-ALL. As ETP-ALL represents a subgroup of early T-ALL we particularly focused on this cohort and identified 178 adult patients enrolled in the German Acute Lymphoblastic Leukemia Multicenter studies (05/93–07/03). Of these, 32% (57/178) were classified as ETP-ALL based on their characteristic immunophenotype. The outcome of adults with ETP-ALL was poor with an overall survival of only 35% at 10 years, comparable to the inferior outcome of early T-ALL with 38%. The molecular characterization of adult ETP-ALL revealed distinct alterations with overexpression of stem cell-related genes (BAALC, IGFBP7, MN1, WT1). Interestingly, we found a low rate of NOTCH1 mutations and no FBXW7 mutations in adult ETP-ALL. In contrast, FLT3 mutations, rare in the overall cohort of T-ALL, were very frequent and nearly exclusively found in ETP-ALL characterized by a specific immunophenotype. These molecular characteristics provide biologic insights and implications with respect to innovative treatment strategies (for example, tyrosine kinase inhibitors) for this high-risk subgroup of adult ETP-ALL.

An early thymic precursor phenotype predicts outcome exclusively in HOXA-overexpressing adult T-cell acute lymphoblastic leukemia: a Group for Research in Adult Acute Lymphoblastic Leukemia study

“…5,6 This immature cluster shows a high level of enrichment of transcripts that are associated with early thymic precursor (ETP)-ALL, 22 a subgroup of T-ALL that exhibit a stem cell/immature myeloid-like immunophenotype, resistance to treatment and poor outcome. 15,[23][24][25][26] Genomic analysis of ETP-ALL has revealed high rates of mutations in factors involved in cytokine receptor and RAS signaling, hematopoiesis and epigenetic modification, 15 but the precise molecular basis of these patients' adverse prognosis remains unclear.…”

CD34 Positive Pediatric T Lymphoblastic Leukemia: A Tertiary Care Centre Experience

“…Recent genetic studies have shed new light on the biology of early T cell precursor acute lymphoblastic leukemia (ETP-ALL), a distinct disease entity associated with poor prognosis and defined by a characteristic immunophenotype and a gene expression signature indicative of a very early arrest in T cell development (24) . N eumann M et al has also identified this as a high risk subtype of T ALL expressing a high rate of FLT3 mutation in adults (25) Molecular studies in pediatric CD34…”

Stat5 is critical for the development and maintenance of myeloproliferative neoplasm initiated by Nf1 deficiency

“…[62][63][64][65] Like acute myeloid leukemia, most ETP ALL harbor mutations that activate RAS and RAS pathway components. 63,65,66 JAK1 and JAK3 are also commonly mutated in ETP ALL.…”