Highlights
- •A novel t(4;13) translocation with 13q14/4q21 flanking deletions is found in CLL.
- •The 4q21 deletion leads to the ARHGAP24 tumor suppressor gene down-regulation.
- •No additional mutation was found, indicating the relevance of the t(4;13) in CLL.
- •The t(4;13) persisted in the blood karyotype from the CLL onset to its regression.
- •The combination of 13q14/4q21 aberrations has a favorable prognostic impact in CLL.
Abstract
13q14 deletion is the most recurrent chromosomal aberration reported in B-CLL, having
a favorable prognostic significance when occurring as the sole cytogenetic alteration.
However, its clinical outcome is also related to the deletion size and number of cells
with the del(13)(q14) deletion. In 10% of cases, 13q14 deletion arises following a
translocation event with multiple partner chromosomes, whose oncogenic impact has
not been investigated so far due to the assumption of a possible role as a passenger
mutation.
Here, we describe a t(4;13)(q21;q14) translocation occurring in a B-CLL case from
the diagnosis to spontaneous regression. FISH and SNP-array analyses revealed a heterozygous
deletion at 4q21, leading to the loss of the Rho GTPase Activating Protein 24 (ARHGAP24) tumor suppressor gene, down-regulated in the patient RNA, in addition to the homozygous
deletion at 13q14 involving DLEU2/miR15a/miR16–1 genes. Interestingly, targeted Next Generation Sequencing analysis of 54 genes related
to B-CLL indicated no additional somatic mutation in the patient, underlining the
relevance of this t(4;13)(q21;q14) aberration in the leukemogenic process.
In all tested RNA samples, RT-qPCR experiments assessed the downregulation of the
PCNA, MKI67, and TOP2A proliferation factor genes, and the BCL2 anti-apoptotic gene as well as the up-regulation of TP53 and CDKN1A tumor suppressors, indicating a low proliferation potential of the cells harboring
the aberration. In addition, RNA-seq analyses identified four chimeric transcripts
(ATG4B::PTMA, OAZ1::PTMA, ZFP36::PTMA, and PIM3::BRD1), two of which (ATG4B::PTMA and ZFP36::PTMA) failed to be detected at the remission, suggesting a possible transcriptional remodeling
during the disease course. Overall, our results indicate a favorable prognostic impact
of the described chromosomal aberration, as it arises a permissive molecular landscape
to the spontaneous B-CLL regression in the patient, highlighting ARHGAP24 as a potentially relevant concurrent alteration to the 13q14 deletion in delineating
B-CLL disease evolution.
Keywords
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Article info
Publication history
Published online: January 06, 2023
Accepted:
January 5,
2023
Received in revised form:
December 6,
2022
Received:
April 20,
2022
Identification
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