Journal Article

Oncogenetic landscape of T-cell lymphoblastic lymphomas compared to T-cell acute lymphoblastic leukemia

Macintyre, Elizabeth, Lengliné, Etienne, Touzart, Aurore, Garnier, Nathalie, Bontoux, Christophe, Baruchel, André, Boissel, Nicolas, Bertrand, Yves, Simonin, Mathieu, Andrieu, Guillaume, Plesa, Adriana, Molina, Thierry Jo, Bruneau, Julie, Asnafi, Vahid, Lhermitte, Ludovic

2022

Overview

In the latest 2016 World Health Organization classification of hematological malignancies, T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) are grouped together into one entity called T-cell lymphoblastic leukemia/lymphoma (T-LBLL). However, the question of whether these entities represent one or two diseases remains. Multiple studies on driver alterations in T-ALL have led to a better understanding of the disease while, so far, little data on genetic profiles in T-LBL is available. We sought to define recurrent genetic alterations in T-LBL and provide a comprehensive comparison with T-ALL. Targeted whole-exome next-generation sequencing of 105 genes, multiplex ligation-dependent probe amplification, and quantitative PCR allowed comprehensive genotype assessment in 818, consecutive, unselected, newly diagnosed patients (342 T-LBL vs. 476 T-ALL). The median age at diagnosis was similar in T-LBL and T-ALL (17 vs. 15 years old, respectively; p = 0.2). Although we found commonly altered signaling pathways and co-occurring mutations, we identified recurrent dissimilarities in actionable gene alterations in T-LBL as compared to T-ALL. HOX abnormalities (TLX1 and TLX3 overexpression) were more frequent in T-ALL (5% of T-LBL vs 13% of T-ALL had TLX1 overexpression; p = 0.04 and 6% of T-LBL vs 17% of T-ALL had TLX3 overexpression; p = 0.006). The PI3K signaling pathway was significantly more frequently altered in T-LBL as compared to T-ALL (33% vs 19%; p < 0.001), especially through PIK3CA alterations (9% vs 2%; p < 0.001) with PIK3CAH1047 as the most common hotspot. Similarly, T-LBL genotypes were significantly enriched in alterations in genes coding for the EZH2 epigenetic regulator and in TP53 mutations (respectively, 13% vs 8%; p = 0.016 and 7% vs 2%; p < 0.001). This genetic landscape of T-LBLL identifies differential involvement of recurrent alterations in T-LBL as compared to T-ALL, thus contributing to better understanding and management of this rare disease.

• Publisher: Elsevier Inc,Nature Publishing Group US,Elsevier Limited,Nature Publishing Group: Open Access Hybrid Model Option B
• Subject: 1-Phosphatidylinositol 3-kinase / 13/31 / 13/51 / 13/56 / 38 / 38/22 / 38/23 / 38/39 / 631/67/69 / 692/420/755 / 692/699/67/1990/283/2125 / Acute lymphoblastic leukemia / Adolescent / Carcinogenesis - pathology / Cell Transformation, Neoplastic - pathology / Class I Phosphatidylinositol 3-Kinases / Epigenetics / Genotypes / Human health and pathology / Humans / Laboratory Medicine / Leukemia / Leukemia-Lymphoma, Adult T-Cell - pathology / Life Sciences / Lymphocytes T / Lymphoma / Lymphoma, T-Cell / Medicine / Medicine & Public Health / Mutation / Next-generation sequencing / p53 Protein / Pathology / Phosphatidylinositol 3-Kinases / Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology / Rare diseases / Signal transduction / T-Lymphocytes - pathology / Tlx1 protein / Tlx3 protein