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Ikaros transcripts Ik6/10 and levels of full-length transcript are critical for chronic myeloid leukaemia blast crisis transformation

Leukemia volume 28, pages 1745–1747 (2014)Cite this article

Ikaros is a zinc finger DNA-binding protein and transcription factor encoded by the IKZF1 gene. Ikaros is a central regulator of haematopoiesis, primarily identified to target key genes mediating cell-fate decisions of pluripotent haematopoietic stem cells into lymphoid pathways. There is evidence that Ikaros regulates the self-renewal of the long-term reconstituting subset of haematopoietic stem cells,1 commitment between erythroid and myeloid cells and early neutrophil differentiation.2 The IKZF1 gene, located at chromosome 7p12, has a number of transcript isoforms due to alternative splicing or genomic deletions. Ikaros isoforms differ in the presence of a DNA-binding domain at the N-terminal or of an activation domain between the DNA-binding domain and the C-terminal protein interaction domain2 (Supplementary Figure 1). It has been shown that 15–20% of paediatric B-acute lymphoblastic leukaemia (B-ALL) and >75% of BCR-ABL1-positive B-ALL are characterised by IKZF1 deletion.3, 4, 5 IKZF1 deletions are associated with a poor overall survival and high frequency of relapse in paediatric B-ALL and adult B-ALL.6 However, it is recently emerging that Ikaros has an important role not only in lymphoid malignancies but also in myeloid leukaemogenesis such as in M4 or M5 acute myeloid leukaemia (AML)7 or in post myeloproliferative neoplasm (MPN) AML.8

BCR-ABL1 tyrosine kinase inhibitors including imatinib, nilotinib and dasatinib have markedly improved the clinical outcome of chronic myeloid leukaemia (CML). However, we have shown recently in a population study that there are still significant numbers of patients (35%) who fail imatinib treatment and some progressed to blast crisis (BC; 3.1%).9 CML blast crisis is characterised by karyotypic evolution with a high frequency of additional cytogenetic abnormalities, such as trisomy 8, trisomy 19, isochromosome 17q, duplication of the Philadelphia chromosome (Ph) and so on.10 However, the molecular mechanism underlying transformation is still largely unknown. It is likely the consequence of progressive genomic instability or epigenetic changes of CML progenitor cells that lead to acquired loss of haematopoietic cell differentiation. A variety of mutations have been associated with progression to BC, including BCR-ABL1 tyrosine kinase domain mutations, p53 and p16 mutations, and more recently characterised mutations such as IKZF1, RUNX1, ASXL1, WT1, TET2, IDH1, NRAS, KRAS and CBL.11 IKZF1 deletion has been identified as a recurrent gene abnormality in CML BC11 and can be detected in both myeloid and lymphoid BC.4, 5 Deletions of IKZF1 coding exons 2–7 can result in the expression of short forms of IKZF1 including the dominant-negative Ik6 (Δ4–7) and the Ik10 (Δ2–7), which has no translational start site. It has been demonstrated that the mRNA expression of these non-DNA-binding Ikaros isoforms arises from IKZF1 genomic abnormalities and not aberrant splicing.3, 4, 5 The expression of Ik6 and Ik10 was exclusively observed in cases harbouring the IKZF1 Δ4–7 deletion 8 and IKZF1 Δ2–7, respectively.

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Authors and Affiliations

  1. Department of Haematology, Royal Liverpool University Hospital, Liverpool, UK

    L Wang

  2. Department of Molecular and Cancer Medicine, Section of Haematology, University of Liverpool, Liverpool, UK

    L Wang, A Howarth & R E Clark

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  1. L Wang
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Correspondence to R E Clark.

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Wang, L., Howarth, A. & Clark, R. Ikaros transcripts Ik6/10 and levels of full-length transcript are critical for chronic myeloid leukaemia blast crisis transformation. Leukemia 28, 1745–1747 (2014). https://doi.org/10.1038/leu.2014.99

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