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IGH rearrangements in Down syndrome acute lymphoblastic leukemia

Lookup NU author(s): Professor Anthony MoormanORCiD

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Abstract

© 2025 The Authors. Background: The IGH locus is susceptible to translocations or insertions that contribute to B-cell precursor acute lymphoblastic leukemia (ALL) by ectopic or enhanced expression of a gene relocated to the IGH enhancer. The frequency of IGH rearrangements is relatively high in Down syndrome (DS) ALL. IGH rearrangements can be cryptic and might not be detected as a chimeric transcript, hence, their frequency, partner genes and prognostic value are largely unknown. Methods: We performed RNA-sequencing and IGH break-apart fluorescent in-situ hybridization (FISH) to determine the genetic and clinical characteristics of IGH rearrangements in 50 DS ALL patients. Results: We identified 10 patients with a chimeric IGH transcript and another 22 IGH-rearranged patients solely by FISH. The IGH rearrangement was clonal (≥ 50 % of leukemic cells) in 11 cases and subclonal (10–50 % of cells) in 21 cases. Almost one-third of the subclonal IGH rearrangements co-occurred with known oncogenic driver aberration. The partner gene was identified in 16 cases and the most frequent partners were CEBPD (n = 6) and CRLF2 (n = 4). A trend towards a worse event-free survival was seen for DS ALL patients with a clonal IGH rearrangement (clonal: HR 3.34, p = 0.053; subclonal: HR 1.80, p = 0.31) compared with DS ALL patients without an IGH rearrangement. Conclusion: By combining RNA-sequencing and FISH, we identified IGH rearrangements in 64 % (n = 32) of DS ALL. A clonal IGH rearrangement (22 %) may point to an unfavorable outcome in DS ALL.

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Author(s): Michels N, Admiraal J, Boeree A, Sonneveld E, Moorman AV, Escherich G, Sutton R, Beverloo HB, Pieters R, Zwaan CM, den Boer ML, Boer JM

Publication type: Article

Publication status: Published

Journal: EJC Paediatric Oncology

Year: 2025

Volume: 5

Print publication date: 01/06/2025

Online publication date: 25/02/2025

Acceptance date: 21/02/2025

ISSN (electronic): 2772-610X

Publisher: Elsevier BV

URL: https://doi.org/10.1016/j.ejcped.2025.100223

DOI: 10.1016/j.ejcped.2025.100223

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