HIF-1α: a potential treatment target in chronic lymphocytic leukemia

Seiffert, Martina

doi:10.3324/haematol.2019.246330

Cited by 7 publications

(9 citation statements)

References 17 publications

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“…Thus, increased hypoxia could contribute to the emergence of phospho‐profile II and its p53‐mutant‐like character. Given the increasing evidence of the importance of the hypoxia pathway in CLL pathogenesis and its potential druggability [54,55], our results point to the possibility of hypoxia pathway targeting even in wt‐ TP53 patients.…”

Section: Discussionmentioning

confidence: 68%

Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage

et al. 2022

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TP53 gene abnormalities represent the most important biomarker in chronic lymphocytic leukemia (CLL). Altered protein modifications could also influence p53 function, even in the wild‐type protein. We assessed the impact of p53 protein phosphorylations on p53 functions as an alternative inactivation mechanism. We studied p53 phospho‐profiles induced by DNA‐damaging agents (fludarabine, doxorubicin) in 71 TP53‐intact primary CLL samples. Doxorubicin induced two distinct phospho‐profiles: profile I (heavily phosphorylated) and profile II (hypophosphorylated). Profile II samples were less capable of activating p53 target genes upon doxorubicin exposure, resembling TP53‐mutant samples at the transcriptomic level, whereas standard p53 signaling was triggered in profile I. ATM locus defects were more common in profile II. The samples also differed in the basal activity of the hypoxia pathway: the highest level was detected in TP53‐mutant samples, followed by profile II and profile I. Our study suggests that wild‐type TP53 CLL cells with less phosphorylated p53 show TP53‐mutant‐like behavior after DNA damage. p53 hypophosphorylation and the related lower ability to respond to DNA damage are linked to ATM locus defects and the higher basal activity of the hypoxia pathway.

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Section: Discussionmentioning

confidence: 68%

Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage

et al. 2022

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“…Our findings demonstrate for the first time that HIF-1α-LVBU-p53 axis in mediating urea cycle for promoting cancer growth. On the basis of its important functions in cancers, HIF-1α is an important therapeutic target for cancer treatment [ 29 ]. However, no HIF-1α inhibitor has been clinically approved so far [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the basis of its important functions in cancers, HIF-1α is an important therapeutic target for cancer treatment [ 29 ]. However, no HIF-1α inhibitor has been clinically approved so far [ 29 ]. Giving its effect in regulating LVBU and urea cycle in cancer, reemphasizing the need of developing HIF-1α inhibitors in cancer therapeutic design is necessary.…”

Section: Discussionmentioning

confidence: 99%

Roles of lncRNA LVBU in regulating urea cycle/polyamine synthesis axis to promote colorectal carcinoma progression

et al. 2022

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Altered expression of Urea Cycle (UC) enzymes occurs in many tumors, resulting a metabolic hallmark termed as UC dysregulation. Polyamines are synthesized from ornithine, and polyamine synthetic genes are elevated in various tumors. However, the underlying deregulations of UC/ polyamine synthesis in cancer remain elusive. Here, we characterized a hypoxia-induced lncRNA LVBU (lncRNA regulation via BCL6/urea cycle) that is highly expressed in colorectal cancer (CRC) and correlates with poor cancer prognosis. Increased LVBU expression promoted CRC cells proliferation, foci formation and tumorigenesis. Further, LVBU regulates urea cycle and polyamine synthesis through BCL6, a negative regulator of p53. Mechanistically, overexpression of LVBU competitively bound miR-10a/miR-34c to protect BCL6 from miR-10a/34c-mediated degradation, which in turn allows BCL6 to block p53-mediated suppression of genes (arginase1 ARG1, ornithine transcarbamylase OTC, ornithine decarboxylase 1 ODC1) involved in UC/polyamine synthesis. Significantly, ODC1 inhibitor attenuated the growth of patient derived xenografts (PDX) that sustain high LVBU levels. Taken together, elevated LVBU can regulate BCL6-p53 signaling axis for systemic UC/polyamine synthesis reprogramming and confers a predilection toward CRC development. Our data demonstrates that further drug development and clinical evaluation of inhibiting UC/polyamine synthesis are warranted for CRC patients with high expression of LVBU.

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“…The hypoxia pathway plays an essential role in lymphocyte development. 25 HIF-1α participates in the integration of the TCR and cytokine receptor-mediated signals of CD4 + helper lineage (eg, the activation of P13 kinase/mTOR pathway) as well as in CD8 + effectors differentiation, in a fashion independent of oxygen availability. 26 CD4 + helper T cells play a critical role in normal immune responses as well as in allergic and autoimmune diseases.…”

Section: Discussionmentioning

confidence: 99%

Single Nucleotide Polymorphisms of the HIF1A Gene are Associated With Sensitivity of Glucocorticoid Treatment in Pediatric ITP Patients

Gu¹,

Xie

Ma³

et al. 2022

Journal of Pediatric Hematology/Oncology

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Background: Hypoxia-inducible factor-1α (HIF-1α) plays a crucial role in both innate and adaptive immunity. Emerging evidence indicates that HIF-1α is associated with the inflammation and pathologic activities of autoimmune diseases, suggesting that HIF1α may be involved in immune dysregulation in patients with immune thrombocytopenia (ITP). The purpose of this study was to evaluate whether single nucleotide polymorphisms (SNPs) of the HIF1A gene are associated with susceptibility to ITP and its clinical prognosis including incidence of chronic ITP and glucocorticoid sensitivity. Materials and Methods:This study involved 197 Chinese ITP pediatric patients (discovery cohort) and 220 healthy controls. The Sequenom MassArray system (Sequenom, San Diego, CA) was used to detect 3 SNPs genotypes in the HIF1A gene: rs11549465, rs1957757, and rs2057482. We also used another ITP cohort (N = 127) to validate the significant results of SNPs found in the discovery cohort.Results: The frequencies of the three SNPs did not show any significant differences between the ITP and healthy control groups. The CT genotype at rs11549465 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (P = 0.025). These results were validated using another ITP cohort (N = 127, P = 0.033). Moreover, the CC genotype was a risk factor for insensitive to GT the odds ratio (95% confidence interval) was 5.96 (5.23-6.69) in standard prednisone (P = 0.0069) and 6. 35 (5.33-7.37) in high-dose dexamethasone (P = 0.04).Conclusions: Although HIF1A gene polymorphisms were not associated with susceptibility to ITP, the CT genotype at rs11549465 was associated with the sensitivity to glucocorticoid treatment of ITP patients, suggesting that the rs11549465 SNP may contribute to the sensitivity of glucocorticoid treatment in pediatric ITP patients.

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HIF-1α: a potential treatment target in chronic lymphocytic leukemia

Cited by 7 publications

References 17 publications

Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage

Distinct p53 phosphorylation patterns in chronic lymphocytic leukemia patients are reflected in the activation of circumjacent pathways upon DNA damage

Roles of lncRNA LVBU in regulating urea cycle/polyamine synthesis axis to promote colorectal carcinoma progression

Single Nucleotide Polymorphisms of the HIF1A Gene are Associated With Sensitivity of Glucocorticoid Treatment in Pediatric ITP Patients

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