title: Leukemic blasts with the paroxysmal nocturnal hemoglobinuria phenotype in children with acute lymphoblastic leukemia.
abstract: It has been proposed that genomic instability is essential to account for the multiplicity of mutations often seen in malignancies. Using the X-linked PIG-A gene as a sentinel gene for spontaneous inactivating somatic mutations, we previously showed that healthy individuals harbor granulocytes with the PIG-A mutant (paroxysmal nocturnal hemoglobinuria) phenotype at a median frequency (f) of ∼12 × 10(-6). Herein, we used a similar approach to determine f in blast cells derived from 19 individuals with acute lymphoblastic leukemia (ALL) and in immortalized Epstein-Barr virus-transformed B-cell cultures (human B-lymphoblastoid cell lines) from 19 healthy donors. The B-lymphoblastoid cell lines exhibited a unimodal distribution, with a median f value of 11 × 10(-6). In contrast, analysis of the f values for the ALL samples revealed at least two distinct populations: one population, representing approximately half of the samples (n = 10), had a median f value of 13 × 10(-6), and the remaining samples (n = 9) had a median f value of 566 × 10(-6). We conclude that in ALL, there are two distinct phenotypes with respect to hypermutability, which we hypothesize will correlate with the number of pathogenic mutations required to produce the leukemia.
authors.affiliation: Division of Hematology, New York University School of Medicine, New York University Langone Clinical Cancer Center, New York, USA. david.araten@nyumc.org
authors.forename: David J
authors.initials: DJ
authors.lastname: Araten
authors.forename: Katie J
authors.initials: KJ
authors.lastname: Sanders
authors.forename: Dan
authors.initials: D
authors.lastname: Anscher
authors.forename: Leah
authors.initials: L
authors.lastname: Zamechek
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Sherif
authors.initials: S
authors.lastname: Ibrahim
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000473:pathology; D001752:Blast Crisis / Q000150:complications* / Q000473:pathology*; D016022:Case-Control Studies; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D005260:Female; D005434:Flow Cytometry; D006457:Hemoglobinuria, Paroxysmal / Q000150:complications* / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000473:pathology*; D014019:Tissue Donors; D055815:Young Adult