Unique role of DDX41, a DEAD-box type RNA helicase, in hematopoiesis and leukemogenesis

Shinriki, Satoru; Matsui, Hirotaka

doi:10.3389/fonc.2022.992340

Cited by 10 publications

(3 citation statements)

References 87 publications

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“… 1 Deleterious germ line DDX41 variants include truncating alleles, which comprise about two-thirds of such variants, missense variants encoding changes within the DEAD-box domain, and deletions ( Figure 1 ). 1 , 4 , 10 , 11 , 12 Interestingly, very rare congenital cases caused by biallelic deleterious germ line variants have been reported. 22 When molecular profiling panels for MNs include DDX41 , the identification of a DDX41 variant should prompt further assessment.…”

Section: Clinical Observationsmentioning

confidence: 99%

DDX41-associated susceptibility to myeloid neoplasms

Makishima

Bowman

Godley

2023

Blood

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Deleterious germline DDX41 variants confer risk for myeloid neoplasms (MNs), and less frequently to lymphoid malignancies, with autosomal dominant inheritance and an estimated prevalence of 3% among MNs. Germline DDX41 variants include truncating alleles that comprise about two thirds of all alleles; missense variants located preferentially within the DEAD box domain; and deletion variants. The identification of a truncating allele on tumor-based molecular profiling should prompt germline genetic testing, since virtually all such alleles are germline. Somatic mutation of the wild-type DDX41 allele occurs in about half of MNs with germline DDX41 alleles, typically in exons encoding the helicase domain and most frequently as R525H. Several aspects of deleterious germline DDX41 alleles are noteworthy: (i) Certain variants are common in particular populations; (ii) MNs develop at older ages typical of de novo disease, challenging the paradigm that inherited cancer risk always causes disease in young people; (iii) Despite equal frequencies of these variants in men and women, men progress to MNs more frequently, suggesting a gender-specific effect on myeloid leukemogenesis; and (iv) Individuals with deleterious germline DDX41 variants develop acute severe graft versus host disease after allogeneic hematopoietic cell transplantation with wild-type donors more than others unless they receive post-transplant cyclophosphamide, suggesting a pro-inflammatory milieu that stimulates donor-derived T-cells. Biochemical studies and animal models have identified DDX41's ability to interact with double stranded DNA and RNA:DNA hybrids with roles in mRNA splicing, rRNAs/snoRNAs processing, and modulation of innate immunity, disruption of which could promote inflammation and drive tumorigenesis.

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Section: Clinical Observationsmentioning

confidence: 99%

DDX41-associated susceptibility to myeloid neoplasms

Makishima

Bowman

Godley

2023

Blood

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“…Of special note, DDX41 plays a significant role in myeloid malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Mutations in DDX41 are found in approximately 2-5% of AML and MDS patients, highlighting its importance in these conditions [233].…”

Section: Oncohematologymentioning

confidence: 99%

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

Korneenko,

Pestov,

Nevzorov

et al. 2023

Pharmaceuticals

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The evolutionary conserved DNA-sensing cGAS-STING innate immunity pathway represents one of the most important cytosolic DNA-sensing systems that is activated in response to viral invasion and/or damage to the integrity of the nuclear envelope. The key outcome of this pathway is the production of interferon, which subsequently stimulates the transcription of hundreds of genes. In oncology, the situation is complex because this pathway may serve either anti- or pro-oncogenic roles, depending on context. The prevailing understanding is that when the innate immune response is activated by sensing cytosolic DNA, such as DNA released from ruptured micronuclei, it results in the production of interferon, which attracts cytotoxic cells to destroy tumors. However, in tumor cells that have adjusted to significant chromosomal instability, particularly in relapsed, treatment-resistant cancers, the cGAS–STING pathway often supports cancer progression, fostering the epithelial-to-mesenchymal transition (EMT). Here, we review this intricate pathway in terms of its association with cancer progression, giving special attention to pancreatic ductal adenocarcinoma and gliomas. As the development of new cGAS–STING-modulating small molecules and immunotherapies such as oncolytic viruses involves serious challenges, we highlight several recent fundamental discoveries, such as the proton-channeling function of STING. These discoveries may serve as guiding lights for potential pharmacological advancements.

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“…Recent reviews outline our current understanding of the roles of DDX41 mutations in myeloid neoplasms (79)(80)(81)(82), which is also briefly elucidated in the subsequent texts. DDX41 probably has multiple biological functions; for more than a decade, it has been suggested that DDX41 is a nucleic acid sensor in the cytoplasm (83,84).…”

Section: R-loop Accumulation In Myeloid Neoplasms With Rna Helicase M...mentioning

confidence: 99%

R-loops in normal and malignant hematopoiesis

Hirayama,

Shinriki,

Matsui

2023

Front. Hematol.

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An R-loop is a nucleic acid structure consisting of a DNA : RNA hybrid and single-stranded DNA. It is formed physiologically in normal cells and is involved in transcription, replication, and gene rearrangement; in particular, it has multiple roles including in mitochondrial DNA replication and class switch recombination of immunoglobulin genes in B cells. However, accumulating evidence indicates aberrant R-loop formation in various malignancies, including hematopoietic neoplasms. The accumulation of such inappropriate R-loops can cause conflicts between transcription and DNA replication. This exacerbates genomic instability through the generation of DNA replication stress, that, in turn, leads to cellular phenotypic changes and disease progression. When RNAs are synthesized during transcription they hybridize with template DNA in cis, giving rise to R-loops. In addition, it was recently revealed that noncoding RNAs also form R-loops when bound to genomic DNA in trans. Together with such observations, new roles for the R-loop in disease development have been proposed. The relationship between inflammation and the R-loop has also attracted much attention. In this review, we will focus on the mechanisms of R-loop formation in various hematopoietic neoplasms and introduce the important findings from recent studies. Therapeutic concepts for targeting R-loop accumulation in hematopoietic neoplasms will also be discussed.

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Unique role of DDX41, a DEAD-box type RNA helicase, in hematopoiesis and leukemogenesis

Cited by 10 publications

References 87 publications

DDX41-associated susceptibility to myeloid neoplasms

DDX41-associated susceptibility to myeloid neoplasms

At the Crossroads of the cGAS-cGAMP-STING Pathway and the DNA Damage Response: Implications for Cancer Progression and Treatment

R-loops in normal and malignant hematopoiesis

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