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

Gaillard, Coline; Surianarayanan, Sangeetha; Bentley, Trevor; Warr, Matthew R.; Fitch, Briana; Geng, Huimin; Passegué, Emmanuelle; Kogan, Scott C.

doi:10.1182/bloodadvances.2018018929

Cited by 16 publications

(14 citation statements)

References 21 publications

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“…It regulates lineage-committed progenitors to promote monocyte maturation and to suppress neutrophil production [10,11]. IRF8 has previously been described to function as a tumor suppressor in multiple cancer types [12,13], including chronic myeloid leukemia (CML) [14][15][16][17] and murine acute promyelocytic leukemia (APL), a subclass of AML [18,19]. In contrast, our investigations suggest a proproliferative role of IRF8 in AML cell lines and connects high IRF8 expression with poorer patient outcome.…”

Section: Introductionmentioning

confidence: 71%

“…Among these genes are well-known factors important for AML, including FLT3, SPI1, RUNX1, and RUNX2 [4,47], demonstrating that the chosen approach is suitable to identify susceptibility genes. Besides these already known factors involved in AML progression, we also identified several novel candidates, including the interferon regulatory factor 8 (IRF8, also ICSBP) ( Figure 1D), which has been described as a tumor suppressor in several other cancer types before [12][13][14][15][16][17][18]. As we were able to identify a putative pro-proliferative and negative prognostic role of IRF8 in AML, we hypothesized that IRF8′s role in AML might vary from its function in other cancer types.…”

Section: Irf8 Is a Susceptibility Gene Candidate In Amlmentioning

confidence: 92%

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IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Liss

Frech

Wang

et al. 2021

Cancers

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Personalized treatment of acute myeloid leukemia (AML) that target individual aberrations strongly improved the survival of AML patients. However, AML is still one of the most lethal cancer diseases of the 21st century, demonstrating the need to find novel drug targets and to explore alternative treatment strategies. Upon investigation of public perturbation data, we identified the transcription factor IRF8 as a novel AML-specific susceptibility gene in humans. IRF8 is upregulated in a subset of AML cells and its deletion leads to impaired proliferation in those cells. Consistently, high IRF8 expression is associated with poorer patients’ prognoses. Combining gene expression changes upon IRF8 deletion and the genome-wide localization of IRF8 in the AML cell line MV4-11, we demonstrate that IRF8 directly regulates key signaling molecules, such as the kinases SRC and FAK, the transcription factors RUNX1 and IRF5, and the cell cycle regulator Cyclin D1. IRF8 loss impairs AML-driving signaling pathways, including the WNT, Chemokine, and VEGF signaling pathways. Additionally, many members of the focal adhesion pathway showed reduced expression, providing a putative link between high IRF8 expression and poor prognosis. Thus, this study suggests that IRF8 could serve as a biomarker and potential molecular target in a subset of human AMLs.

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Section: Introductionmentioning

confidence: 71%

Section: Irf8 Is a Susceptibility Gene Candidate In Amlmentioning

confidence: 92%

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Liss

Frech

Wang

et al. 2021

Cancers

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“…Together with somatic mutations, aberrantly expressed genes have been identified in APL patients. For example, a recent study has revealed that the down-regulation of IRF8 driven by PML-RARA could trigger the advent and preservation of the leukemic clone in a mouse model, contributing to the acquisition of cooperative genomic events [42]. In addition, the expression profile of genes such as ID1, BAALC, ERC, WT1 and KMT2E, alongside additional molecular events (such FLT3-ITD status and ∆Np73/TAp73 expression ratio), could improve the treatment outcome prediction in high-risk APL patients ( Figure 2).…”

Section: Gene Mutations At Diagnosis Relapse and Resistancementioning

confidence: 99%

“…On the one hand, PML-RARA produces a block of myeloid differentiation at the promyelocytic stage [40,41]. In this case, PML-RARA represses the transcription of several genes implicated in myeloid differentiation, such as those involved in the differentiation towards the granulocyte lineage, in a manner insensitive to physiological levels of retinoic ligands [42,43]. On the other hand, PML-RARA confers a survival and proliferative advantage to leukemic cells, resulting in the progressive accumulation of promyelocytes in the bone marrow of APL patients [36,44].…”

Section: Introductionmentioning

confidence: 99%

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

Liquori

Ibáñez

Sargas

et al. 2020

Cancers

107

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Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the PML-RARA rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as FLT3, WT1, NRAS and KRAS, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the PML-RARA fusion gene, could contribute to the 10%-15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as ID1, BAALC, ERG, and KMT2E, once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease.

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“…IRF8 is a master transcription factor driving differentiation and function of DCs including CD141 Hi cDCs [ 25 – 27 ]. We and others have shown that IRF8 expression is reduced in bulk progenitors from patients with myeloid malignancies [ 28 – 31 ]. We compared expression of IRF8 in HD versus MDS HSPC populations.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells

et al. 2020

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The use of immunotherapy to treat patients with myelodysplastic syndromes (MDS) shows promise but is limited by our incomplete understanding of the immunologic milieu . In solid tumors, CD141 Hi conventional dendritic cells (CD141 Hi cDCs) are necessary for anti-tumor immunosurveillance and the response to immunotherapy. Here, we found that CD141 Hi cDCs are reduced in MDS bone marrow and based on the premise established in solid tumors, we hypothesized that reduced numbers of CD141 Hi cDCs are associated with inferior overall survival in MDS patients. We found that MDS patients with reduced numbers of CD141 Hi cDCs, but not other DC populations, showed reduced overall survival. To examine the basis for reduction in CD141 Hi cDCs, we found fewer numbers of progenitors committed to DC differentiation in the MDS bone marrow and these progenitors expressed lower levels of interferon regulatory factor-8 (IRF8), a master regulator of CD141 Hi cDC differentiation. To rescue impaired CD141 Hi cDC differentiation, we used pharmacologic inhibition of lysine-specific demethylase 1A (LSD1) to promote CD141 Hi cDC differentiation by MDS progenitors. These data reveal a previously unrecognized element of the MDS immunologic milieu . Epigenetic regulation of CD141 Hi cDC differentiation offers an intriguing opportunity for intervention and a potential adjunct to immunotherapy for patients with MDS.

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

Cited by 16 publications

References 21 publications

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

IRF8 Is an AML-Specific Susceptibility Factor That Regulates Signaling Pathways and Proliferation of AML Cells

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

Inhibition of LSD1 in MDS progenitors restores differentiation of CD141Hi conventional dendritic cells

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