Adult Low-Hypodiploid Acute Lymphoblastic Leukemia Emerges from Preleukemic<i>TP53</i>-Mutant Clonal Hematopoiesis

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<jats:title>Abstract</jats:title><jats:sec><jats:title /><jats:p>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.</jats:p></jats:sec><jats:sec><jats:title>Significance:</jats:title><jats:p>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.</jats:p><jats:p>See related commentary by Saiki and Ogawa, p. 102.</jats:p><jats:p>This article is highlighted in the In This Issue feature, p. 101</jats:p></jats:sec>

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  • Blood Cancer Discovery

    Blood Cancer Discovery 4 134-149, 2023-01-10

    American Association for Cancer Research (AACR)

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