Expression of aberrantly spliced oncogenic Ikaros isoforms coupled with clonal IKZF1 deletions and chimeric oncogenes in acute lymphoblastic leukemia

IKZF1 deletions associate with CRLF2 overexpression leading to a poor prognosis in B-cell precursor acute lymphoblastic leukaemia

“…However, functional experiments are necessary to confirm this hypothesis. The finding that CRLF2 expression was higher in the IKZF1 plus when compared to the IKZF1 wt subgroup goes along with the idea of both being poor prognostic markers and more frequently found within the ‘B-other’ subgroup [ 2 , 9 , 10 , 13 ].…”

“…On the other hand, the isoforms that lose two or more of these ZFs, are unable to bind DNA, but they retain their capability to form heterodimers with IKZF1 long isoforms leading to a dominant-negative effect. Physiologically, IKZF1 directly binds to the CRLF2 promoter and suppresses its expression through enrichment of H3K9me3 (represented by the red cross in the figure) [ 9 , 10 , 26 ]. …”

“…Exons 4-6 of IKZF1 code DNA-binding zinc finger domains, while exon 8 codes a zinc finger dimerization domain. Alternative splicing of IKZF1 mRNA generates at least 13 different variants, including both long (IK1-IK3) and short (IK4-IK10) isoforms [10] . Those isoforms play different roles depending on their DNA-binding ability.…”

Detection by a simple and cheaper methodology of Ik6 and Ik10 isoforms of the IKZF1 gene is highly associated with a poor prognosis in B‐lineage paediatric acute lymphoblastic leukaemia

“…The short isoforms (Ik4 to Ik10) lack two or more zinc‐finger domains, thus being unable to bind to DNA, impairing the function of IKAROS proteins and behaving as a negative domain (Vshyukova et al , ). Ik6 is the most common form of shorter isoforms, being able to suppress DNA binding function and is the strongest transcription repressor in the Ikaros family.…”

Phenotypical and Functional Characteristics of Human Regulatory T Cells during Ex Vivo Maturation from CD4+ T Lymphocytes

“…The remarkable phenotypical consistency of Tregs is associated with stable demethylation in the CpG-rich specific demethylated region (TSDR) within the FoxP3 promoter, which promotes proliferation and differentiation of Tregs [7,8]. IKAROS family zinc member transcription factors [9], along with reactivation of telomerase [10], also have well-documented roles in the development of immune cell populations, and the process of alternative splicing of their pre-mRNA has a significant impact on cellular biology [11][12][13].…”