Targeting Heme Oxygenase-1 Improves Poor Therapeutical Outcomes of BCR-ABL-Positive Adult B-Allwithikaros Isoform 6

Genomic profiling studies have demonstrated that the dominant-negative Ikaros isoform 6 (IK6) is overexpressed in BCR-ABL1-positive B-lineage acute lymphoblastic leukemia (BCR-ABL1-positive B-ALL), and it is strongly associated with a poor outcome. In addition, IK6 expression leads to BCR-ABL-positive B-ALL patients insensitive to tyrosine kinase inhibitors (TKIs). Moreover, a study has revealed that Heme oxygenase-1 (HO-1), an essential survival factor, could be a potential target in treating ALL. Therefore, we were wondering whether targeting HO-1 could improve poor therapeutical outcomes of BCR-ABL-positive adult B-ALL with IK6. Firstly, we detected that IK6 existed in 20 of 42 (47.6%) adult BCR-ABL1-positive B-ALL by using reverse transcribed polymerase chain reaction (PCR) and nucleotide sequencing. We also found that early clinical response was poor in BCR-ABL1-positive B-ALL patients with IK6, and they were usually high WBC counts at diagnosis and a high relapse rate. Compared to healthy donors' CD34⁺ cells, the levels of HO-1 expression were higher in primary CD34⁺ cells derived from adult BCR-ABL1-positive B-ALL patients with IK6 by qRT-PCR and western blot studies. And there was a strong correlation between the expression of IK6 and HO-1. In primary CD34⁺ leukemic cells derived from our IK6-positive patients' pool, silencing HO-1 resulted in the reduce of proliferation and a substantial proapoptotic effect, including a significantly enriched subG1 population, an increase of Annexin V-positive cells and of caspase3 cleavage. Furthermore, silencing HO-1 also increased their sensitivity to TKIs. This phenomenon was also supported by the observation that ZnPP IX substantially augmented the growth-inhibitory effects of imatinib on primary leukemic cells. Finally, we found that IK6 led to STAT5 activiation, and HO-1 was one of the downstream target genes of STAT5. In conclusion, the existence of extra IK6 seems to exacerbate poor prognosis and risks of relapse in adult BCR-ABL1-positive B-ALL. HO-1 plays an important role as a survival factor in BCR-ABL1-positive B-ALL with IK6, and targeting HO-1 can probably improve the clinical outcomes.