Research Papers:

Targeting of heme oxygenase-1 attenuates the negative impact of Ikaros isoform 6 in adult BCR-ABL1-positive B-ALL

Xiaojing Lin, Xingli Zou, Ziming Wang, Qin Fang, Shuya Chen, Jun Huang, Nana Zhe, Meisheng Yu, Yaming Zhang and Jishi Wang _

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Oncotarget. 2016; 7:53679-53701. https://doi.org/10.18632/oncotarget.10725

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Xiaojing Lin1,5, Xingli Zou5, Ziming Wang2,3, Qin Fang4, Shuya Chen1,2,3, Jun Huang1,2,3, Nana Zhe1,2,3, Meisheng Yu1,2,3, Yaming Zhang2,3, Jishi Wang1,2,3

1Clinical Medicine, Guizhou Medical University, Guiyang 550004, China

2Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China

3Department of Hematology, Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China

4Department of Pharmacy, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550004, China

5Department of Hematology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China

Correspondence to:

Jishi Wang, email: wangjishi9646@163.com

Keywords: acute lymphoblastic leukemia, BCR-ABL1-positive, heme oxygenase-1, IKZF1, STAT5

Received: September 16, 2015    Accepted: June 07, 2016    Published: July 20, 2016


The correlation between Heme oxygenase-1 (HO-1) and dominant-negative Ikaros isoform 6 (IK6) is unclear. Firstly, we detected that IK6 existed in 20 of 42 (47.6%) adult BCR-ABL1-positive B-lineage acute lymphoblastic leukemia (BCR-ABL1-positive B-ALL) by using reverse transcribed polymerase chain reaction (PCR) and nucleotide sequencing. IK6-positive patients had an unfavorable outcome compared with IK6-negative ones. Further study showed that the level of HO-1 expression was higher in IK6-positive patients’ samples than that in IK6-negative ones. And there was a strong correlation between the expression of IK6 and HO-1. The growth of primary CD34+ leukemic cells derived from our IK6-positive patients’ pool was prohibited by silencing HO-1, further promoting their apoptosis. Furthermore, primary CD34+ leukemic cells derived from IK6-positive patients shown poor responses to imatinib in comparison with wild-type (IK1) patients, suggesting that the expression of IK6 resisted to imatinib in adult BCR-ABL1-positive B-ALL. Importantly, inhibition of HO-1 also increased their sensitivity to tyrosine kinase inhibitors (TKIs). Finally, we found that IK6 activated downstream STAT5, and HO-1 was one of the downstream target genes of STAT5. In conclusion, HO-1 is an essential survival factor in BCR-ABL1-positive B-ALL with IK6, and targeting HO-1 can attenuate the negative impact of IK6.

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