The IKZF1 gene on the short-arm of chromosome 7 codes for IKAROS, a hematopoietic transcription factor with an essential role in lymphoid differentiation. It rose to prominence in 2009 when multiple groups discovered recurrent focal deletions in its exons11,12, and has since remained in the spotlight owing to its adverse prognosis leading to high treatment failure13.

Recurrent somatic IKZF1 deletions have now been shown to occur predominantly in B-cell ALL (up to 70-80% in Ph+ B-ALL), CML in lymphoid blast crisis (about 70%), and to a lesser extent in T-cell ALL and AML14. IKZF1 might also have a role in myeloid leukemogenesis with evidence of recurrent deletions observed in childhood AML, MPN and MDS patients progressing to AML, as well as therapy-related AML in adults15. Further, monosomy 7 also results in IKZF1 copy number variation and is considered to contribute to the negative prognosis in pediatric and adult AML.blood-75301_640

Finally, aberrant expression and hypermethylation of IKZF1 has been noted in a significant proportion of tumours of the neuroendocrine system and large intestine, though their clinical significance is yet to be elucidated14. The recurrent translocation affecting IKZF1 in diffuse large B-cell lymphoma is known, but the disease characteristic is attributed to aberrant BCL6 expression as a consequence of the translocation.

In leukemia, there is a diverse presentation of ΔIKZF1 genotypes. Monosomy 7 and loss of the p-arm of chromosome 7, both lead to haploid copy number of IKZF1 gene and are known adverse prognostic factors16. These constitute only up to 5% of the causes of ΔIKZF1 and are best detected by karyotyping. Similarly, whole gene deletions comprising all exons also appear to be a small minority. The largest population of ΔIKZF1, also with the highest clinical impact, is constituted by focal deletions of exons 4-7 and exons 2-716,17. Deletion of exon 2 leads to haploinsufficiency and thus copy number aberration, whereas Δ4-7 leads to dominant negative IKZF1 isoforms, which might have an arguably lower, albeit significantly adverse, clinical impact. Deletions of other exons also occur at low frequencies. Four of the most common exonic deletions contribute about 80-85% of all ΔIKZF1 and are clinically important. Point mutations of the coding regions have also been reported in some studies with varying prevalence of 1-2% and their clinical impact will depend on the individual mutation17.

The picture is further complicated by the presence of both biclonal as well as biallelic deletions in 20% of patients16. While biallelic deletions, unsurprisingly, have a greater adverse impact, this may be complicated by the kind of mutation present. One of the best designed studies that addressed the impact of deletion type on prognosis concluded that common and rare deletion variants indicate significantly high risk (HR of 1.4-2.3)13. But the authors did not comment on non-deletion mutations of IKZF1.

This diversity of the mutational landscape of IKZF1 poses challenges in terms of its diagnosis. While MLPA (multiplex ligation probe-dependent amplification) is the standard for detection of multiple focal deletions, PCR for targeted deletions comprising the vast majority of isoforms offers significantly higher sensitivity and remains a valid alternative, including for MRD detection. Cytogenetics, as mentioned, will only detect monosomy 7 and the rare loss of 7p. For all the rarer mutations including obscure deletions and point mutations, deep sequencing for copy number variation and mutations might be required, and understandably, this has been resorted to only in a minority of the publications.

IKZF1 deletions by themselves are not leukemogenic and may thus be a secondary mutation, as some individuals were found with constitutional deletions in IKZF1 without clinical impact14. Having said that, the importance of diagnosing IKZF1 deletions stems from its high clinical impact in terms of adverse prognosis, predicting treatment failure and risk of relapse, as well as possibly guiding therapy intensification or modification.

Majority of the studies focus on B-cell ALL because of the high prevalence, especially among Ph+ and Ph+-like B-ALL, where ΔIKZF1 is seen in 75% of patients18,19. The deletion leads to significantly lower event-free survival and overall survival through 10-year periods. It has also emerged as the strongest predictor of treatment failure, relapse and death independent of other factors such as WBC count, MRD and age18,20. Further, the adverse prognosis held true irrespective of imatinib treatment, where patients with deletion were found not to respond to tyrosine kinase inhibitors as well as IKZF1wt patients19.

In AML, IKZF1 deletion may play a role in MDS and MPN progression to AML, but any resulting adverse impact vis-à-vis AML patients without deletion is unclear with reports of worse disease outcome as well as lack of significant impact15.

With regard to therapeutic outcome, at least one group has recently shown that vincristine steroid pulses during maintenance phase in patients with deletion significantly improved their 8-year event-free survival (93% vs. 42%)21, so much so that the outcome of these patients was similar to the IKZF1wt group. A strong argument for the use of retinoid receptor agonists in ΔIKZF1 comes from preclinical research22, where this was further found to potentiate TKI activity, particularly dasatinib, in models with Ph+ B-ALL. Nevertheless, outcome with steroid pulses needs to be independently reproduced and retinoids validated in clinical trials before their adoption into clinical practice.

About 70% of patients in CML with lymphoid blast crisis may harbor IKZF1 deletions, with their absence during the chronic phase suggesting a causative or additive role of this mutation23. Identifying these high-risk patients beforehand would be beneficial because of the TKI-refractory role of IKZF1 deletion24. Although the likelihood of IKAROS mutation due to deficient activity in advanced CML was detected over 15 years ago25, therapy and outcome studies are still lacking, and are likely to gain from the strides made in B-cell ALL.


11. Martinelli G, Iacobucci I, Storlazzi CT, et al. IKZF1 (Ikaros) deletions in BCR-ABL1-positive acute lymphoblastic leukemia are associated with short disease-free survival and high rate of cumulative incidence of relapse: A GIMEMA AL WP report. J Clin Oncol. 2009;27(31):5202-5207. doi:10.1200/JCO.2008.21.6408.

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25.         Nakayama H, Ishimaru F, Avitahl N, et al. Decreases in Ikaros activity correlate with blast crisis in patients with chronic myelogenous leukemia. Cancer Res. 1999;59(16):3931-3934.