Myeloid neoplasms and clonal hematopoiesis from the RUNX1 perspective

Hayashi, Yoshihiro; Harada, Yuka; Harada, Hironori

doi:10.1038/s41375-022-01548-7

Cited by 14 publications

(11 citation statements)

References 146 publications

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“…However, the regulation of the expression level between the RUNX1/2/3 transcription factors was reported [ 161 ], leading to the overexpression of RUNX2 in case of RUNX1 loss, which promoted pDC differentiation, IRF7 expression and increased antigen presentation and ZEB 1 and 2 expression loss [ 19 , 161 , 162 ]. Moreover, RUNX1 loss of function induced dysregulated innate immune signaling [ 163 ]. MYD88-NF-κB signaling activated by TLR and IRAK4/TRAF6 recruitment led to NLR protein 3 (NLRP3) activation, adaptor apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) and pro-caspase-1 recruitment, and NLRP3-inflammasome formation, leading to caspase-1 activation and inflammatory cell death such as pyroptosis and necroptosis [ 164 , 165 ].…”

Section: Current Therapies and Perspective In Pdc-amlmentioning

confidence: 99%

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

Roussel

Ottou

Renosi

2022

Cancers

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Plasmacytoid dendritic cells (pDC) are the main type I interferon producing cells in humans and are able to modulate innate and adaptive immune responses. Tumor infiltration by plasmacytoid dendritic cells is already well described and is associated with poor outcomes in cancers due to the tolerogenic activity of pDC. In hematological diseases, Blastic Plasmacytoid Dendritic Cells Neoplasm (BPDCN), aggressive leukemia derived from pDCs, is well described, but little is known about tumor infiltration by mature pDC described in Myeloid Neoplasms (MN). Recently, mature pDC proliferation (MPDCP) has been described as a differential diagnosis of BPDCN associated with acute myeloid leukemia (pDC-AML), myelodysplastic syndrome (pDC-MDS) and chronic myelomonocytic leukemia (pDC-CMML). Tumor cells are myeloid blasts and/or mature myeloid cells from related myeloid disorders and pDC derived from a clonal proliferation. The poor prognosis associated with MPDCP requires a better understanding of pDC biology, MN oncogenesis and immune response. This review provides a comprehensive overview about the biological aspects of pDCs, the description of pDC proliferation in MN, and an insight into putative therapies in pDC-AML regarding personalized medicine.

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Section: Current Therapies and Perspective In Pdc-amlmentioning

confidence: 99%

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

Roussel

Ottou

Renosi

2022

Cancers

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“…RUNX1 is a critical transcription factor for hematopoiesis; RUNX1 mutation is recurrently detected and is a poor prognostic marker in myeloid malignancies (24). FPD-MM is the first HMMs whose genetic causality was recognized in 1999 (20).…”

Section: Runx1mentioning

confidence: 99%

Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation

Toya

Harada

et al. 2022

Front. Oncol.

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Hereditary myeloid malignancies, especially in adults or elderly persons, had been considered quite rare before the next-generation sequencing era; however, increased usage of clinical sequencing has revealed much higher prevalence of inherited myeloid malignancies. DDX41 and various pathogenic germline mutations have newly been recognized as the cause of adult-onset familial leukemia and myeloid malignancies. Although germline predisposition to myeloid neoplasms had been categorized as a provisional entity in the World Health Organization classification of hematopoietic neoplasms in 2016, methodology for the identification of hereditary myeloid malignancies has not been fully established yet. In addition, many unresolved problems, such as epidemiology, the exact pathogenic mechanisms, and ideal treatment strategy, including indications of allogeneic hematopoietic stem cell transplantation, still remain. Related donor selection for stem cell transplant is a particularly sensitive issue due to the possibility of germline mutation of the candidate relatives and the risk of donor cell leukemia after transplantation. Here, we reviewed the current evidence regarding epidemiology, diagnosis, mechanisms of progression, and transplantation strategy for hereditary myeloid malignancies.

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“…Developmental processes in the hematopoietic compartment are mainly regulated at the transcriptional level [ 1 , 2 ]. Accordingly, specific transcription factors (TFs) control differentiation into mature immune cells along the myeloid lineage, for example, CEBPA, GATA1, GATA2, HOXA9, RUNX1/AML1, and SPI1/PU.1 [ 3 , 4 , 5 , 6 , 7 ]. Deregulation of these TFs via chromosomal rearrangements or gene mutations generates myeloid malignancies, highlighting their pathogenic significance [ 3 , 4 , 5 , 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Accordingly, specific transcription factors (TFs) control differentiation into mature immune cells along the myeloid lineage, for example, CEBPA, GATA1, GATA2, HOXA9, RUNX1/AML1, and SPI1/PU.1 [ 3 , 4 , 5 , 6 , 7 ]. Deregulation of these TFs via chromosomal rearrangements or gene mutations generates myeloid malignancies, highlighting their pathogenic significance [ 3 , 4 , 5 , 6 , 7 ]. Therefore, investigation of developmental TFs is likely to promote understanding of both normal myelopoiesis and myeloid tumorigenesis.…”

Section: Introductionmentioning

confidence: 99%

Establishment of the Myeloid TBX-Code Reveals Aberrant Expression of T-Box Gene TBX1 in Chronic Myeloid Leukemia

Nagel,

Haake,

Pommerenke

et al. 2023

IJMS

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T-box genes encode transcription factors, which control developmental processes and promote cancer if deregulated. Recently, we described the lymphoid TBX-code, which collates T-box gene activities in normal lymphopoiesis, enabling identification of members deregulated in lymphoid malignancies. Here, we have extended this analysis to cover myelopoiesis, compiling the myeloid TBX-code and, thus, highlighting which of these genes might be deregulated in myeloid tumor types. We analyzed public T-box gene expression datasets bioinformatically for normal and malignant cells. Candidate T-box-gene-expressing model cell lines were identified and examined by RQ-PCR, Western Blotting, genomic profiling, and siRNA-mediated knockdown combined with RNA-seq analysis and live-cell imaging. The established myeloid TBX-code comprised 10 T-box genes, including progenitor-cell-restricted TBX1. Accordingly, we detected aberrant expression of TBX1 in 10% of stem/progenitor-cell-derived chronic myeloid leukemia (CML) patients. The classic CML cell line K-562 expressed TBX1 at high levels and served as a model to identify TBX1 activators, including transcription factor GATA1 and genomic amplification of the TBX1 locus at 22q11; inhibitors, including BCR::ABL1 fusion and downregulated GNAI2, as well as BMP, FGF2, and WNT signaling; and the target genes CDKN1A, MIR17HG, NAV1, and TMEM38A. The establishment of the myeloid TBX-code permitted identification of aberrant TBX1 expression in subsets of CML patients and cell lines. TBX1 forms an integral part of an oncogenic regulatory network impacting proliferation, survival, and differentiation. Thus, the data spotlight novel diagnostic markers and potential therapeutic targets for this malignancy.

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Myeloid neoplasms and clonal hematopoiesis from the RUNX1 perspective

Cited by 14 publications

References 146 publications

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

Plasmacytoid Dendritic Cells, a Novel Target in Myeloid Neoplasms

Adult-onset hereditary myeloid malignancy and allogeneic stem cell transplantation

Establishment of the Myeloid TBX-Code Reveals Aberrant Expression of T-Box Gene TBX1 in Chronic Myeloid Leukemia

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