All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells

Liu, Xiang-Zhen; Chen, Juan; Yu, Shanhe; Li, Yan; Guo, Hongbo; Dai, Jian-Min; Zhang, Wu; Zhu, Jiang

doi:10.1038/cddis.2017.197

Cited by 16 publications

(15 citation statements)

References 39 publications

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“…To bridge this gap, a recently published study demonstrated that overexpression of IRF8 in leukemic cells from our MRP8-PML/RARA mouse model 7 inhibits transplantation of established leukemia. 19 Our work complements existing data to indicate an important role for IRF8 suppression in APL pathogenesis. Altogether, our data support a model of APL leukemogenesis in which the translocation of chromosomes 15 and 17 initiates leukemia development, in part by downregulating IRF8, and in which the resulting expansion of the promyelocyte compartment contributes to acquisition of additional cooperating events (eg, trisomy of chromosome 8, 20 mutation of FLT3 21 ) that complete leukemic transformation.…”

Section: Resultssupporting

confidence: 79%

Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

Gaillard¹,

Surianarayanan²,

Bentley³

et al. 2018

Blood Advances

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Although the role of promyelocytic leukemia/retinoic acid receptor α (PML/RARA) fusion protein is well recognized in acute promyelocytic leukemia (APL), its contribution to initiation and maintenance of leukemogenesis is not completely understood. Transcriptome analysis in the murine MRP8-PML/RARA APL model has demonstrated modest alterations in gene expression accompanied by expansion of the promyelocyte compartment. Of particular interest, mice expressing PML/RARA showed downregulation of the transcription factor Irf8 mRNA. Interferon regulatory factor 8 (IRF8) is a known regulator of hematopoiesis. Previous research had implicated IRF8 as a tumor suppressor for myeloid neoplasia, and mice lacking IRF8 develop a well-differentiated myeloproliferative neoplasm characterized by expansion of neutrophilic lineage cells. We hypothesized that PML/RARA-mediated downregulation of Irf8 transcript levels contributes to the initiation of APL. We observed significant downregulation of IRF8 protein levels in highly purified promyelocyte populations of PML/RARA transgenic mice. We also found that loss of IRF8 results in expansion of promyelocytes in vivo, partially phenocopying the impact of PML/RARA expression. Moreover, survival experiments showed that complete loss of IRF8 leads to acceleration of APL onset in our PML/RARA mice. Collectively, these data identify IRF8 downregulation as an important factor in APL initiation and highlight a tumor-suppressor role for IRF8 in this acute leukemia.

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Section: Resultssupporting

confidence: 79%

Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

Gaillard¹,

Surianarayanan²,

Bentley³

et al. 2018

Blood Advances

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“…HMRP8-PML-RARa transgenic mice were generated on an FVB/NJ background using the human MRP8 expression cassette (23). The reproducible APL transplantation model can be propagated by injecting APL blasts, isolated from hMRP8-PML-RARa transgenic mice, into the tail vein of syngeneic recipients (24). All transplanted APL cells were highly purified by flow-sorting to exclude the dying cells, and then injected into the immunodeficient mice or syngeneic recipients.…”

Section: Cells and Micementioning

confidence: 99%

TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance

Lin

Niu

et al. 2019

Clinical Cancer Research

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Purpose: The resistance to differentiation therapy and early death caused by fatal bleeding endangers the health of a significant proportion of patients with acute promyelocytic leukemia (APL). This study aims to investigate the molecular mechanisms of all-trans retinoic acid (ATRA) resistance and uncover new potential therapeutic strategies to block the rapid progression of early death. Experimental Design: The important role of TWIST1 in APL leukemogenesis was first determined by gain-and lossof-function assays. We then performed in vivo and in vitro experiments to explore the interaction of TWIST1 and TRIB3 and develop a potential peptide-initiated therapeutic opportunity to protect against early death and induction therapy resistance in patients with APL. Results: We found that the epithelial-mesenchymal transition (EMT)-inducing transcription factor TWIST1 is highly expressed in APL cells and is critical for leukemic cell survival. TWIST1 and TRIB3 were highly coexpressed in APL cells compared with other subtypes of acute myeloid leukemia cells. We subsequently demonstrated that TRIB3 could bind to the WR domain of TWIST1 and contribute to its stabilization by inhibiting its ubiquitination. TRIB3 depletion promoting TWIST1 degradation reverses resistance to induction therapy and improves sensitivity to ATRA. On the basis of a detailed functional screen of synthetic peptides, we discovered a peptide analogous to the TWIST1 WR domain that specifically represses APL cell survival by disrupting the TRIB3/TWIST1 interaction. Conclusions: Our data not only define the essential role of TWIST1 as an EMT-TF in patients with APL but also suggest that disrupting the TRIB3/TWIST1 interaction reverses induction therapy resistance and blocks rapid progression of APL early death. See related commentary by Peeke and Gritsman, p. 6018

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“…Tretinoin, a derivative of Vitamin A, can function via targeting the retinoic acid receptor alpha (RARα)-mediated signals to alter the cell apoptosis [17], and has been used as a medication to treat acute promyelocytic leukemia (APL) for decades [18]. However, its linkage to altering the TR4mediated signals remains unclear.…”

Section: Introductionmentioning

confidence: 99%

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

Shi

Sun

et al. 2019

Oncogene

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Renal cell carcinoma (RCC) is one of the most lethal urological tumors. Using sunitinib to improve the survival has become the first-line therapy for metastatic RCC patients. However, the occurrence of sunitinib resistance in the clinical application has curtailed its efficacy. Here we found TR4 nuclear receptor might alter the sunitinib resistance to RCC via altering the TR4/lncTASR/AXL signaling. Mechanism dissection revealed that TR4 could modulate lncTASR (ENST00000600671.1) expression via transcriptional regulation, which might then increase AXL protein expression via enhancing the stability of AXL mRNA to increase the sunitinib resistance in RCC. Human clinical surveys also linked the expression of TR4, lncTASR, and AXL to the RCC survival, and results from multiple RCC cell lines revealed that targeting this newly identified TR4-mediated signaling with small molecules, including tretinoin, metformin, or TR4-shRNAs, all led to increase the sunitinib sensitivity to better suppress the RCC progression, and our preclinical study using the in vivo mouse model further proved tretinoin had a better synergistic effect to increase sunitinib sensitivity to suppress RCC progression. Future successful clinical trials may help in the development of a novel therapy to better suppress the RCC progression.

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All-trans retinoic acid and arsenic trioxide fail to derepress the monocytic differentiation driver Irf8 in acute promyelocytic leukemia cells

Cited by 16 publications

References 39 publications

Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

Identification of IRF8 as a potent tumor suppressor in murine acute promyelocytic leukemia

TRIB3 Stabilizes High TWIST1 Expression to Promote Rapid APL Progression and ATRA Resistance

Targeting the TR4 nuclear receptor-mediated lncTASR/AXL signaling with tretinoin increases the sunitinib sensitivity to better suppress the RCC progression

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