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Oncotarget. 2016 Aug 16;7(33):53679-53701. doi: 10.18632/oncotarget.10725.

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

Lin X1,2, Zou X2, Wang Z3,4, Fang Q5, Chen S1,3,4, Huang J1,3,4, Zhe N1,3,4, Yu M1,3,4, Zhang Y3,4, Wang J1,3,4.

Author information

1
Clinical Medicine, Guizhou Medical University, Guiyang 550004, China.
2
Department of Hematology, The Affiliated Hospital of North Sichuan Medical College, Nanchong 637000, China.
3
Department of Hematology, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.
4
Department of Hematology, Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China.
5
Department of Pharmacy, The Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550004, China.

Abstract

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.

KEYWORDS:

BCR-ABL1-positive; IKZF1; STAT5; acute lymphoblastic leukemia; heme oxygenase-1

PMID:
27447561
PMCID:
PMC5288214
DOI:
10.18632/oncotarget.10725
[Indexed for MEDLINE]
Free PMC Article

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