3205 – A ROLE FOR IKZF1 IN PRE-LEUKEMIC T-ALL?

T-cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T-cell development, as result of a multistep oncogenic process, involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Here, we report the identification of a novel CDK6-IKZF1 fusion gene, using targeted locus amplification with IKZF1 as a viewpoint, in a glucocorticoid resistant immature T-ALL patient. Further characterization of this fusion gene showed a non-functional CDK6-IKZF1 protein, therefore we hypothesized that heterozygous loss-of-function mutations of CDK6 or IKZF1 might actually be the real drivers in T-ALL. First, we evaluated the impact of loss of Ikzf1 in a spontaneous CD2-Lmo2 T-ALL mouse model. Interestingly, heterozygous loss of Ikzf1 collaborates with CD2-Lmo2, whilst homozygous loss of Ikzf1 on its own is sufficient to induce T-ALL independently of Lmo2 overexpression. This suggests that loss of Ikzf1 is a mechanism that can maintain self-renewal properties of T-ALL lymphoblasts. In addition, we also looked at the effect of heterozygous Cdk6 loss in a spontaneous CD2-Lmo2 T-ALL mouse model, as some reports in literature show the presence of CDK6 fusion genes or deletions in T-ALL. However, our results show no significant difference in tumor latency between CD2-Lmo2Tg/+ Cdk6+/+ and CD2-Lmo2Tg/+ Cdk6KO/+ mice, concluding that heterozygous loss of Cdk6 is no driver mutation in T-ALL. In conclusion, our results indicate that Ikzf1 might play a pivotal role in acquiring thymic self-renewal properties. Fundamental insights on Ikzf1-related self-renewal could provide valuable input for the development of novel therapeutic strategies that can effectively target therapy-resistant clones in T-ALL. T-cell acute lymphoblastic leukemias (T-ALLs) arise from the malignant transformation of hematopoietic progenitors primed toward T-cell development, as result of a multistep oncogenic process, involving constitutive activation of NOTCH signaling and genetic alterations in transcription factors, signaling oncogenes, and tumor suppressors. Here, we report the identification of a novel CDK6-IKZF1 fusion gene, using targeted locus amplification with IKZF1 as a viewpoint, in a glucocorticoid resistant immature T-ALL patient. Further characterization of this fusion gene showed a non-functional CDK6-IKZF1 protein, therefore we hypothesized that heterozygous loss-of-function mutations of CDK6 or IKZF1 might actually be the real drivers in T-ALL. First, we evaluated the impact of loss of Ikzf1 in a spontaneous CD2-Lmo2 T-ALL mouse model. Interestingly, heterozygous loss of Ikzf1 collaborates with CD2-Lmo2, whilst homozygous loss of Ikzf1 on its own is sufficient to induce T-ALL independently of Lmo2 overexpression. This suggests that loss of Ikzf1 is a mechanism that can maintain self-renewal properties of T-ALL lymphoblasts. In addition, we also looked at the effect of heterozygous Cdk6 loss in a spontaneous CD2-Lmo2 T-ALL mouse model, as some reports in literature show the presence of CDK6 fusion genes or deletions in T-ALL. However, our results show no significant difference in tumor latency between CD2-Lmo2Tg/+ Cdk6+/+ and CD2-Lmo2Tg/+ Cdk6KO/+ mice, concluding that heterozygous loss of Cdk6 is no driver mutation in T-ALL. In conclusion, our results indicate that Ikzf1 might play a pivotal role in acquiring thymic self-renewal properties. Fundamental insights on Ikzf1-related self-renewal could provide valuable input for the development of novel therapeutic strategies that can effectively target therapy-resistant clones in T-ALL.