Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production

Weinreb, Joshua; Ghazale, Noura; Pradhan, Kith; Gupta, Varun; Potts, Kathryn; Tricomi, Brad; Daniels, Noah J.; Padgett, Richard A.; Oliveira, Sofía de; Verma, Amit; Bowman, Teresa V.

doi:10.1016/j.devcel.2021.02.006

Cited by 63 publications

(77 citation statements)

References 74 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 12 The molecular pathway was unveiled that insufficient DDX41 enabled R-loops to accumulate, hence triggering inflammatory signaling and finally empowering hematopoietic cells to increase. 7 Here we analyzed the clinical aspects of DDX41 -mutated diseases, which is the first systematic review along with IPD about this mutation at least to date. Although unable to conduct a meta-analysis due to a large portion of missing data, we presented a larger dataset of individual patients with comprehensive searching.…”

Section: Discussionmentioning

confidence: 99%

“… 6 Recently, DDX41 in zebrafish was reported to be a crucial gatekeeper of over-producing hematopoietic stem and progenitor cells, by inhibiting excessive R-loops and thus preventing an inflammatory cascade. 7 This study has shed light on how DDX41 mutants lead to a clinically significant subtype of myeloid neoplasms. Moreover, deficient DDX41 in erythroid progenitors would diminish their proliferation and impair differentiation, thus manifesting anemia clinically.…”

Section: Introductionmentioning

confidence: 96%

See 1 more Smart Citation

Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

Wan

Han

2021

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms. Methods: In this study, “ DDX41” was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary. Results: Pooled incidence was 3.3% (95% confidence interval 2.4–4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20–88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed. Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886)

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 96%

Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

Wan

Han

2021

Therapeutic Advances in Hematology

View full text Add to dashboard Cite

show abstract

“…Dead box helicase (DDX41) is a tumor suppressor that is conserved in D.melanogaster, C.elegans, D.rerio and plants, and is considered essential to cell growth and viability [32][33][34][35] .…”

mentioning

confidence: 99%

R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability

Beli

Mosler

Conte

et al. 2021

Preprint

View full text Add to dashboard Cite

Transcription can pose a threat to genomic stability through the formation of R-loops that obstruct the progression of replication forks. R-loops are three-stranded nucleic acid structures formed by an RNA-DNA hybrid with a displaced non-template DNA strand. We developed RDProx to identify proteins that regulate R-loops in human cells. RDProx relies on the expression of the hybrid-binding domain (HBD) of Ribonuclease H1 (RNaseH1) fused to the ascorbate peroxidase (APEX2) and permits mapping of the R-loop proximal proteome using quantitative mass spectrometry. We implicate different cellular proteins in R-loop regulation and identify a role of the tumor suppressor DEAD box protein 41 (DDX41) in opposing R-loop-dependent genomic instability. Depletion of DDX41 resulted in replication stress, double strand breaks and inflammatory signaling. DDX41 opposes the accumulation of R-loops by unwinding RNA-DNA hybrids at gene promoters and its loss leads to upregulation of TGFβ and NOTCH signaling genes. Germline loss-of-function mutations in DDX41 lead to predisposition to acute myeloid leukemia (AML) in adulthood. We propose that accumulation of R-loops at CpG island promoters, altered TGFβ and NOTCH signaling, and inflammatory response contribute to the development of familial AML with mutated DDX41.

show abstract

“…Whole transcriptome profiling in different species shows that DDX41 functions in RNA splicing (1,18,26,27). While our RNASeq data showed that DDX41 had the greatest effects on transcript levels in LSK+ cells, the data also showed that DDX41 loss altered exon skipping and intron retention.…”

Section: Discussionmentioning

confidence: 64%

DDX41 is needed for pre-and post-natal hematopoietic stem cell differentiation in mice

Mahmud

Bosland

et al. 2021

Preprint

View full text Add to dashboard Cite

DDX41 is a tumor suppressor frequently mutated in human myeloid neoplasms. DDX41 binds to DNA/RNA hybrids and interacts with spliceosome components. How it affects hematopoiesis is still unclear. Using a knockout mouse model, we demonstrate that DDX41 is required for mouse hematopoietic stem and progenitor cell (HSPC) survival and differentiation. Lack of DDX41 particularly affected myeloid progenitor development, starting at embryonic day 13.5. Transplantation of DDX41-deficient fetal liver and adult bone marrow (BM) cells were unable to rescue mice from lethal irradiation after transplantation. DDX41 knockout stem cells were also defective in ex vivo colony forming assays. RNASeq analysis of lineage-negative, cKit+Sca1+ cells isolated from fetal liver demonstrated that the expression of many genes associated with hematopoietic differentiation were altered in DDX41 knockout cells. Furthermore, altered splicing of genes involved in key biological processes were observed in cells lacking DDX41. Our data reveal a critical role for DDX41 in HSPC differentiation and myeloid progenitor development, likely through its regulation of gene expression programs and splicing.

show abstract

Excessive R-loops trigger an inflammatory cascade leading to increased HSPC production

Cited by 63 publications

References 74 publications

Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

Clinical features ofDDX41mutation-related diseases: a systematic review with individual patient data

R-loop proximity proteomics identifies a role of DDX41 in transcription-associated genomic instability

DDX41 is needed for pre-and post-natal hematopoietic stem cell differentiation in mice

Contact Info

Product

Resources

About