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

Lin, Xiaojing; Zou, Xing-Li; Wang, Ziming; Fang, Qin; Chen, Shuya; Huang, Jun; Zhe, Nana; Yu, Meisheng; Zhang, Yaming; Wang, Jishi

doi:10.18632/oncotarget.10725

Cited by 9 publications

(8 citation statements)

References 48 publications

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“…HO-1 is an essential survival factor for BCR-ABL1-positive B-ALL, the overexpression of which can enhance the resistance to tyrosine kinase inhibitors. 32 However, the We have previously reported that the resistance of chronic myeloid leukemia to imatinib was mediated by HO-1 overexpression in BMSCs based on increase of SDF-1 secretion. Moreover, HO-1 protected BMSCs from ROS through secreting IL-10 in the case of iron overload.…”

Section: Discussionmentioning

confidence: 97%

“…HO-1 is an essential survival factor for BCR-ABL1-positive B-ALL, the overexpression of which can enhance the resistance to tyrosine kinase inhibitors. 32 However, the F I G U R E 6 Heme oxygenase-1 (HO-1) overexpression in bone marrow microenvironment induced resistant of B-cell acute lymphoblastic leukemia (B-ALL) in vivo. A, Flow cytometry assay the tumor growing in peripheral blood of NOD/SCID mice were transplanted by testing the ratio of human CD45+ cells in peripheral blood cells.…”

Section: Discussionmentioning

confidence: 99%

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Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

Wang

Lü

et al. 2019

J of Cellular Biochemistry

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Chemoresistance often causes treatment failure of B‐cell acute lymphoblastic leukemia (B‐ALL). However, the mechanism remains unclear at present. Herein, overexpression of heme oxygenase‐1 (HO‐1) was found in the bone marrow stromal cells (BMSCs) from B‐ALL patients developing resistance to vincristine (VCR), a chemotherapeutic agent. Two B‐ALL cell lines Super B15 and CCRF‐SB were cocultured with BMSCs transfected with lentivirus to regulate the expression of HO‐1. Silencing HO‐1 expression in BMSCs increased the apoptotic rates of B‐ALL cell lines induced by VCR, whereas upregulating HO‐1 expression reduced the rate. Cell cycle can be arrested in the G2/M phase by VCR. In contrast, B‐ALL cells were arrested in the G0/G1 phase due to HO‐1 overexpression in BMSCs, which avoided damage from the G2/M phase. Vascular endothelial growth factor (VEGF) in BMSCs, as a key factor in the microenvironment‐associated chemoresistance, was also positively coexpressed with HO‐1. VEGF secretion was markedly increased in BMSCs with HO‐1 upregulation but decreased in BMSCs with HO‐1 silencing. B‐ALL cell lines became resistant to VCR when cultured with VEGF recombinant protein, so VEGF secretion induced by HO‐1 expression may promote the VCR resistance of B‐ALL cells. As to the molecular mechanism, the PI3K/AKT pathway mediated regulation of VEGF by HO‐1. In conclusion, this study clarifies a mechanism by which B‐ALL is induced to resist VCR through HO‐1 overexpression in BMSCs, and provides a novel strategy for overcoming VCR resistance in clinical practice.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

Wang

Lü

et al. 2019

J of Cellular Biochemistry

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“…The transcripts of the dominant-negative isoforms Ik6 and Ik8 were detected by nested RT-PCR, based on the methods described by Iacobucci et al [30,31]. The expected sizes of the PCR products of the Ik8 and Ik6 isoforms are 390 and 255 base pairs, respectively.…”

Section: Analysis Of Ik6 and Ik8 Transcriptsmentioning

confidence: 99%

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

Lorenzana

León

et al. 2021

The Journal of Pathology CR

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The gene fusions BCR‐ABL1, TCF3‐PBX1, and ETV6‐RUNX1 are recurrent in B‐cell acute lymphoblastic leukemia (B‐ALL) and are found with low frequency in coexistence with CRLF2 (cytokine receptor‐like factor 2) rearrangements and overexpression. There is limited information regarding the CRLF2 abnormalities and dominant‐negative IKZF1 isoforms associated with surrogate markers of Jak2, ABL, and Ras signaling pathways. To assess this, we evaluated 24 Mexican children with B‐ALL positive for recurrent gene fusions at diagnosis. We found CRLF2 rearrangements and/or overexpression, dominant‐negative IKZF1 isoforms, and surrogate phosphorylated markers of signaling pathways coexisting with recurrent gene fusions. All the BCR‐ABL1 patients expressed CRLF2 and were positive for pCrkl (ABL); most of them were also positive for pStat5 (Jak2/Stat5) and negative for pErk (Ras). TCF3‐PBX1 patients with CRLF2 abnormalities were positive for pStat5, most of them were also positive for pCrkl, and two patients were also positive for pErk. One patient with ETV6‐RUNX1 and intracellular CRLF2 protein expressed pCrkl. In some cases, the activated signaling pathways were reverted in vitro by specific inhibitors. We further analyzed a TCF3‐PBX1 patient at relapse, identifying a clone with the recurrent gene fusion, P2RY8‐CRLF2, rearrangement, and phosphorylation of the three surrogate markers that we studied. These results agree with the previous reports regarding resistance to treatment observed in patients with recurrent gene fusions and coexisting CRLF2 gene abnormalities. A marker phosphorylation signature was identified in BCR‐ABL1 and TCF3‐PBX1 patients. To obtain useful information for the assessment of treatment in B‐ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant‐negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

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“…For example, our laboratory studies the role of the cytoprotective enzyme HO-1 in the prevention of various forms of pre-, post-, and intrinsic-renal AKI. The induction of HO-1 expression provides well documented protection against cisplatin-mediated AKI, 63 but systemic induction of this enzyme is of limited utility in patients with cancer because, despite mixed evidence, 64,65 there is fear that systemic pharmacologic induction of HO-1 will promote cancer cell survival and growth. [66][67][68] However, employing US in patients with cancer receiving cisplatin-based chemotherapy to prevent intrinsic renal injury could be achieved by loading MBs with any one of a number of well described HO-1 inducers 69 and achieving renal-specific delivery with US.…”

Section: Us Treatment Of Kidney Diseasementioning

confidence: 99%

New Ultrasound Techniques Promise Further Advances in AKI and CKD

Hull

Agarwal

Hoyt

2017

JASN

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AKI and CKD are important clinical problems because they affect many patients and the associated diagnostic and treatment paradigms are imperfect. Ultrasound is a cost-effective, noninvasive, and simple imaging modality that offers a multitude of means to improve the diagnosis, monitoring, and treatment of both AKI and CKD, especially considering recent advances in this technique. Ultrasound alone can attenuate AKI and prevent CKD by stimulating the splenic cholinergic anti-inflammatory pathway. Additionally, microbubble contrast agents are improving the sensitivity and specificity of ultrasound for diagnosing kidney disease, especially when these agents are conjugated to ligand-specific mAbs or peptides, which make the dynamic assessment of disease progression and response to treatment possible. More recently, drug-loaded microbubbles have been developed and the load release by ultrasound exposure has been shown to be a highly specific treatment modality, making the potential applications of ultrasound even more promising. This review focuses on the multiple strategies for using ultrasound with and without microbubble technology for enhancing our understanding of the pathophysiology of AKI and CKD.

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

Cited by 9 publications

References 48 publications

Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

Overexpression of heme oxygenase‐1 in microenvironment mediates vincristine resistance of B‐cell acute lymphoblastic leukemia by promoting vascular endothelial growth factor secretion

CRLF2 and IKZF1 abnormalities in Mexican children with acute lymphoblastic leukemia and recurrent gene fusions: exploring surrogate markers of signaling pathways

New Ultrasound Techniques Promise Further Advances in AKI and CKD

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