IGH rearrangements in Down syndrome acute lymphoblastic leukemia

IGH rearrangements in Down syndrome acute lymphoblastic leukemia

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....

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Main Authors: Naomi Michels, Jade Admiraal, Aurélie Boeree, Edwin Sonneveld, Anthony V. Moorman, Gabriele Escherich, Rosemary Sutton, H. Berna Beverloo, Rob Pieters, C. Michel Zwaan, Monique L. den Boer, Judith M. Boer
Format: Article
Language:English
Published: Elsevier 2025-06-01
Series:EJC Paediatric Oncology
Subjects:
Fluorescence in situ hybridization
Pediatric
Down syndrome
RNA sequencing
Online Access:http://www.sciencedirect.com/science/article/pii/S2772610X25000108
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Summary: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.
ISSN:2772-610X

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