Clinico-biological features of T-cell acute lymphoblastic leukemia with fusion proteins

Thomas Steimlé,Hervé Dombret,André Baruchel,Mathieu Simonin,Carlos Graux,Marie Balsat,Elizabeth A Macintyre ,Jean‐Michel Cayuela ,Jonathan Bond,Marie-Émilie Dourthe ,Virginie Gandemer,Nicolas Boissel,Norbert Ifrah,Johanna Mondesir,Aurore Touzart,Arnaud Petit,Ludovic Lhermitte,Nathalie Grardel,Isabelle Arnoux,Norbert Vey,Marion Alcantara,Philippe Ruminy,Vahid Asnafi

doi:10.1038/s41408-022-00613-9

Abstract

T-cell acute lymphoblastic leukemias (T-ALL) represent 15% of pediatric and 25% of adult ALL. Since they have a particularly poor outcome in relapsed/refractory cases, identifying prognosis factors at diagnosis is crucial to adapting treatment for high-risk patients. Unlike acute myeloid leukemia and BCP ALL, chromosomal rearrangements leading to chimeric fusion-proteins with strong prognosis impact are sparsely reported in T-ALL. To address this issue an RT-MPLA assay was applied to a consecutive series of 522 adult and pediatric T-ALLs and identified a fusion transcript in 20% of cases. PICALM-MLLT10 (4%, n = 23), NUP214-ABL1 (3%, n = 19) and SET-NUP214 (3%, n = 18) were the most frequent. The clinico-biological characteristics linked to fusion transcripts in a subset of 235 patients (138 adults in the GRAALL2003/05 trials and 97 children from the FRALLE2000 trial) were analyzed to identify their prognosis impact. Patients with HOXA trans-deregulated T-ALLs with MLLT10, KMT2A and SET fusion transcripts (17%, 39/235) had a worse prognosis with a 5-year EFS of 35.7% vs 63.7% (HR = 1.63; p = 0.04) and a trend for a higher cumulative incidence of relapse (5-year CIR = 45.7% vs 25.2%, HR = 1.6; p = 0.11). Fusion transcripts status in T-ALL can be robustly identified by RT-MLPA, facilitating risk adapted treatment strategies for high-risk patients.

Highlights

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer arising from the transformation of T cell precursors arrested at specific stages of differentiation [1, 2]
Cytogenetic and global transcriptomic analyses led to the classification of T-ALL into molecular subgroups characterized by the abnormal expression of specific transcription factors (TF) (TAL1; LMO1/2; TLX1/3; LYL1; HOXA; MEF2C) and their blocked differentiation at specific stages of maturation [1, 7, 8]
RT-MLPA detect an unexpected 20% incidence of fusion proteins in T-ALLs A series of 522 T-ALL, all systematically screened for PICALMMLLT10, SET-NUP214, and NUP214-ABL1 by RT/qPCR, were evaluated for fusion transcripts by RT-MLPA

Summary

INTRODUCTION

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological cancer arising from the transformation of T cell precursors arrested at specific stages of differentiation [1, 2]. Recurrent chimeric protein fusions in T-ALL include rearrangements of KMT2A (AFDN (AF6), MLLT1, ELL), SET-NUP214, ABL1 (NUP214-ABL1, BCR-ABL1), MLLT10 (PICALM, DDX3X, NAP1L1, XPO1), and the ETS family (SPI and ETV6) Given their individual low frequency, the clinico-biological features of T-ALLs harboring chimeric fusions within a comprehensive series competitive events. All p values were two-sided, with p < 0.05 denoting statistical significance To address this issue, we designed and developed an RT-MPLA assay allowing identification of the majority of known fusion transcripts leading to chimeric proteins in T-ALLs. To address this issue, we designed and developed an RT-MPLA assay allowing identification of the majority of known fusion transcripts leading to chimeric proteins in T-ALLs Applying this panel to a comprehensive, consecutive series of 522 adult and pediatric T-ALLs, we here report an unexpected overall incidence of 20% of fusion transcript. Their mutational landscape, associated clinico-biological features and prognostic impact on patients enrolled in the French GRAALL protocol for adult patients and the FRALLE 2000T protocol for pediatric patients are described

RESULTS

METHODS

DISCUSSION