Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53 -Mutant Clonal Hematopoiesis - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Blood Cancer Discovery Année : 2023

Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53 -Mutant Clonal Hematopoiesis

Hugo Bergugnat
Wendy Cuccuini
Vahid Asnafi
Beat Schäfer
Eric Delabesse
Yosr Hicheri
Yves Chalandon
Carlos Graux
Thibaut Leguay
Véronique Lhéritier
Hervé Dombret
Nicolas Boissel

Résumé

Unlabelled - Low hypodiploidy defines a rare subtype of B-cell acute lymphoblastic leukemia (B-ALL) with a dismal outcome. To investigate the genomic basis of low-hypodiploid ALL (LH-ALL) in adults, we analyzed copy-number aberrations, loss of heterozygosity, mutations, and cytogenetics data in a prospective cohort of Philadelphia (Ph)-negative B-ALL patients (n = 591, ages 18-84 years), allowing us to identify 80 LH-ALL cases (14%). Genomic analysis was critical for evidencing low hypodiploidy in many cases missed by cytogenetics. The proportion of LH-ALL within Ph-negative B-ALL dramatically increased with age, from 3% in the youngest patients (under 40 years old) to 32% in the oldest (over 55 years old). Somatic TP53 biallelic inactivation was the hallmark of adult LH-ALL, present in virtually all cases (98%). Strikingly, we detected TP53 mutations in posttreatment remission samples in 34% of patients. Single-cell proteogenomics of diagnosis and remission bone marrow samples evidenced a preleukemic, multilineage, TP53-mutant clone, reminiscent of age-related clonal hematopoiesis. Significance - We show that low-hypodiploid ALL is a frequent entity within B-ALL in older adults, relying on somatic TP53 biallelic alteration. Our study unveils a link between aging and low-hypodiploid ALL, with TP53-mutant clonal hematopoiesis representing a preleukemic reservoir that can give rise to aneuploidy and B-ALL. See related commentary by Saiki and Ogawa, p. 102. This article is highlighted in the In This Issue feature, p. 101.

Domaines

Cancer Hématologie
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Dates et versions

hal-04090842 , version 1 (26-09-2023)

Identifiants

Citer

Rathana Kim, Hugo Bergugnat, Lise Larcher, Matthieu Duchmann, Marie Passet, et al.. Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic TP53 -Mutant Clonal Hematopoiesis. Blood Cancer Discovery, 2023, 4 (2), pp.134-149. ⟨10.1158/2643-3230.BCD-22-0154⟩. ⟨hal-04090842⟩
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