N-terminus DUX4-immunohistochemistry is a reliable methodology for the diagnosis of DUX4-fused B-lymphoblastic leukemia/lymphoma (N-terminus DUX4 IHC for DUX4-fused B-ALL).
Adolescent and young adult
B-lymphoblastic leukemia
DUX4
immunohistochemistry
Journal
Genes, chromosomes & cancer
ISSN: 1098-2264
Titre abrégé: Genes Chromosomes Cancer
Pays: United States
ID NLM: 9007329
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
15
02
2022
received:
20
09
2021
accepted:
16
02
2022
pubmed:
27
2
2022
medline:
15
6
2022
entrez:
26
2
2022
Statut:
ppublish
Résumé
B-lymphoblastic leukemia/lymphoma (B-ALL) is the most common pediatric malignancy and the most commonly diagnosed adult lymphoblastic leukemia. Recent advances have broadened the spectrum of B-ALL, with DUX4 gene fusions implicated in a subclass occurring in adolescents and young adults and harboring a favorable prognosis. DUX4 fusions have been challenging to identify. We aimed to determine whether expression of the DUX4 oncoprotein, as detected by targeted immunohistochemistry, might serve as a surrogate for molecular detection of DUX4 fusions in B-ALL. A cohort of investigational B-ALLs was generated with enrichment for DUX4 fusions by the inclusion of cases with characteristic demographic features and immunophenotypic properties. B-ALLs with mutually exclusive cytogenetics were collected. Immunohistochemical staining by a monoclonal antibody raised against the N-terminus of the DUX4 protein was performed. N-DUX4 immunohistochemistry demonstrated strong, crisp nuclear staining in blasts of seven investigational cases, six of which had nucleic acid material available for molecular evaluation. Five of these cases demonstrated RNA-seq DUX4-fusion positivity. One N-DUX4 immunohistochemistry positive case lacked a definitive DUX4-fusion by RNA-seq, though demonstrated a gene expression profile characteristic of DUX4-rearranged B-ALLs, a CD2+ immunophenotype, and a lack of staining by C-terminus DUX4 antibody immunohistochemistry. At least 83.3% [5/6] positive predictive value. N-DUX4 immunohistochemistry was negative in blasts of three RNA-seq DUX4-fusion-negative cases (3/3; 100% negative predictive value). B-ALLs with mutually exclusive cytogenetic profiles were all N-DUX4 negative (0/10, specificity 100%). N-DUX4 immunohistochemistry is reliable for the distinction of DUX4-rearranged B-ALLs from other B-ALLs. We recommend its use for subclassification of B-ALLs in adolescents and young adults and in B-ALLs that remain "not otherwise specified."
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
449-458Informations de copyright
© 2022 Wiley Periodicals LLC.
Références
Howlader N, Noone A, Krapcho M, et al., eds. SEER Cancer Statistics Review, 1975-2017. National Cancer Institute; 2020. https://seer.cancer.gov/csr/1975_2017/
Jaffe E, Arber D, Campo E, Quintanilla-Fend L, Orazi A, eds. Hematopathology. 2nd ed. Elsevier; 2017.
Swerdlow S, Campo E, Harris N, et al., eds. WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues. 4th ed. World Health Association; 2017.
Yeoh EJ, Ross ME, Shurtleff SA, et al. Classification, subtype discovery, and prediction of outcome in pediatric acute lymphoblastic leukemia by gene expression profiling. Cancer Cell. 2002;1(2):133-143.
Mullighan CG, Su X, Zhang J, et al. Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia. N Engl J Med. 2009;360(5):470-480.
Dupuis A, Gaub MP, Legrain M, et al. Biclonal and biallelic deletions occur in 20% of B-ALL cases with IKZF1 mutations. Leukemia. 2013;27(2):503-507.
Mullighan CG, Miller CB, Su X, et al. ERG deletions define a novel subtype of B-progenitor acute lymphoblastic leukemia. Blood. 2007;110(11):691.
Li JF, Dai YT, Lilljebjörn H, et al. Transcriptional landscape of B cell precursor acute lymphoblastic leukemia based on an international study of 1,223 cases. Proc Natl Acad Sci U S A. 2018;115(50):E11711-E11720.
Harvey RC, Mullighan CG, Wang X, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874-4884.
Li Z, Lee SHR, Chin WHN, et al. Distinct clinical characteristics of DUX4- and PAX5-altered childhood B-lymphoblastic leukemia. Blood Adv. 2021;5(23):5226-5238.
Zhang J, McCastlain K, Yoshihara H, et al. Deregulation of DUX4 and ERG in acute lymphoblastic leukemia. Nat Genet. 2016;48(12):1481-1489.
Iacobucci I, Mullighan CG. Genetic basis of acute lymphoblastic leukemia. J Clin Oncol. 2017;35(9):975-983.
Yasuda T, Tsuzuki S, Kawazu M, et al. Recurrent DUX4 fusions in B cell acute lymphoblastic leukemia of adolescents and young adults. Nat Genet. 2016;48(5):569-574.
Clappier E, Auclerc MF, Rapion J, et al. An intragenic ERG deletion is a marker of an oncogenic subtype of B-cell precursor acute lymphoblastic leukemia with a favorable outcome despite frequent IKZF1 deletions. Leukemia. 2014;28(1):70-77.
Zaliova M, Zimmermannova O, Dörge P, et al. ERG deletion is associated with CD2 and attenuates the negative impact of IKZF1 deletion in childhood acute lymphoblastic leukemia. Leukemia. 2014;28(1):182-185.
Schinnerl D, Mejstrikova E, Schumich A, et al. CD371 cell surface expression: a unique feature of. Haematologica. 2019;104(8):e352-e355.
Lilljebjörn H, Henningsson R, Hyrenius-Wittsten A, et al. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia. Nat Commun. 2016;7:11790.
Zaliova M, Potuckova E, Hovorkova L, et al. ERG deletions in childhood acute lymphoblastic leukemia with DUX4 rearrangements are mostly polyclonal, prognostically relevant, and their detection rate strongly depends on screening method sensitivity. Haematologica. 2019;104(7):1407-1416.
Siegele B, Roberts J, Black JO, Rudzinski E, Vargas SO, Galambos C. DUX4 immunohistochemistry is a highly sensitive and specific marker for CIC-DUX4 fusion-positive round cell tumor. Am J Surg Pathol. 2017;41(3):423-429.
Antonescu CR, Owosho AA, Zhang L, et al. Sarcomas with CIC-rearrangements are a distinct pathologic entity with aggressive outcome: a clinicopathologic and molecular study of 115 cases. Am J Surg Pathol. 2017;41(7):941-949.
Geng LN, Tyler AE, Tapscott SJ. Immunodetection of human double homeobox 4. Hybridoma. 2011;30(2):125-130.
Hung YP, Fletcher CD, Hornick JL. Evaluation of ETV4 and WT1 expression in CIC-rearranged sarcomas and histologic mimics. Mod Pathol. 2016;29(11):1324-1334.
Hendrickson PG, Doráis JA, Grow EJ, et al. Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL/HERVL retrotransposons. Nat Genet. 2017;49(6):925-934.
Snider L, Geng LN, Lemmers RJ, et al. Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet. 2010;6(10):e1001181.
Tanaka Y, Kawazu M, Yasuda T, et al. Transcriptional activities of DUX4 fusions in B-cell acute lymphoblastic leukemia. Haematologica. 2018;103(11):e522-e526.
Falini B, Mecucci C, Tiacci E, et al. Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352(3):254-266.
Ritterhouse LL, Barletta JA. BRAF V600E mutation-specific antibody: a review. Semin Diagn Pathol. 2015;32(5):400-408.