Oncogenetic landscape and clinical impact of IDH1 and IDH2 mutations in T-ALL

Journal of Hematology & Oncology

Françoise Huguet¹  Carlos Graux²  André Baruchel³  Arnaud Petit⁴  Virginie Gandemer⁵  Nathalie Grardel⁶  Isabelle Arnoux⁷  Jean-Michel Cayuela⁸  Mathieu Simonin⁹  Vahid Asnafi^1,10  Christophe Bontoux^1,10  Elizabeth Macintyre^1,10  Guillaume P. Andrieu^1,10  Ludovic Lhermitte^1,10  Marie-Émilie Dourthe^1,11  Aline Schmidt^1,12  Norbert Ifrah^1,12  Stéphane Ducassou^1,13  Nicolas Boissel^1,14  Etienne Lengliné^1,14  Hervé Dombret^1,14 

[1] Department of Hematology, CHRU - Institut Universitaire de Cancer Toulouse - Oncopole, Toulouse, France;Department of Hematology, Université Catholique de Louvain, CHU UCL Namur - site Godinne, Yvoir, Belgium;Department of Pediatric Hematology and Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Robert Debré Hospital, University Paris Diderot, Paris, France;Department of Pediatric Hematology and Oncology, Assistance Publique-Hôpitaux de Paris (AP-HP), Armand Trousseau Hospital, Sorbonne Université, Paris, France;Department of Pediatric Hematology and Oncology, University Hospital of Rennes, Rennes, France;Laboratory of Hematology, CHRU - Inserm U1172, Lille, France;Inserm U1172, Lille Cedex, France;Laboratory of Hematology, Marseille University Hospital Timone, Marseille, France;Laboratory of Hematology, Saint-Louis Hospital, AP-HP, Paris, France;Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France;Department of Pediatric Hematology and Oncology, Assistance Publique-Hôpitaux de Paris (AP-HP), Armand Trousseau Hospital, Sorbonne Université, Paris, France;Institut Necker-Enfants Malades (INEM), Institut National de la Santé et de la Recherche Médicale (Inserm) U1151, Paris, France;Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France;Institut Necker-Enfants Malades (INEM), Institut National de la Santé et de la Recherche Médicale (Inserm) U1151, Paris, France;Laboratory of Onco-Hematology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Necker Enfants-Malades, Université de Paris, 149 rue de Sèvres, 75015, Paris, France;Institut Necker-Enfants Malades (INEM), Institut National de la Santé et de la Recherche Médicale (Inserm) U1151, Paris, France;Department of Pediatric Hematology and Immunology, Assistance Publique-Hôpitaux de Paris (AP-HP), Robert Debré Hospital, University Paris Diderot, Paris, France;PRES LUNAM, CHU Angers service des Maladies du Sang, INSERM U 892, Angers, France;Pediatric Hematology-Oncology Department, Centre Hospitalier Universitaire (CHU), Bordeaux, France;Université Paris Diderot, Institut Universitaire d’Hématologie, EA-3518, Assistance Publique-Hôpitaux de Paris, University Hospital Saint-Louis, Paris, France;

关键词: IDH1;    IDH2;    T-ALL;   

DOI  :  10.1186/s13045-021-01068-4

来源: Springer

【 摘 要 】

IDH1 and IDH2 mutations (IDH1/2Mut) are recognized as recurrent genetic alterations in acute myeloid leukemia (AML) and associated with both clinical impact and therapeutic opportunity due to the recent development of specific IDH1/2Mut inhibitors. In T-cell acute lymphoblastic leukemia (T-ALL), their incidence and prognostic implications remain poorly reported. Our targeted next-generation sequencing approach allowed comprehensive assessment of genotype across the entire IDH1 and IDH2 locus in 1085 consecutive unselected and newly diagnosed patients with T-ALL and identified 4% of, virtually exclusive (47 of 49 patients), IDH1/2Mut. Mutational patterns of IDH1/2Mut in T-ALL present some specific features compared to AML. Whereas IDH2R140Q mutation was frequent in T-ALL (25 of 51 mutations), the IDH2R172 AML hotspot was absent. IDH2 mutations were associated with older age, an immature phenotype, more frequent RAS gain-of-function mutations and epigenetic regulator loss-of-function alterations (DNMT3A and TET2). IDH2 mutations, contrary to IDH1 mutations, appeared to be an independent prognostic factor in multivariate analysis with the NOTCH1/FBXW7/RAS/PTEN classifier. IDH2Mut were significantly associated with a high cumulative incidence of relapse and very dismal outcome, suggesting that IDH2-mutated T-ALL cases should be identified at diagnosis in order to benefit from therapeutic intensification and/or specific IDH2 inhibitors.

【 授权许可】

CC BY