Table 2.

Contrast of phenotypes in animal vs human studies

	Animal studies	Human observations
Effect on HSPCs	Hypomorphic zebrafish ddx41 mutants display aberrant HSPC expansion, with deregulation of type I IFN pathway components and targets31	Patients present with leukopenia, hypocellular bone marrow, and erythroid dysplasia1
	Mouse Ddx41 KO HSPC show diminished survival and transplantation capacity32,33
	Mouse HSPCs with Ddx41 heterozygous KO show competitive advantage33
	Mice with Ddx41 heterozygous KO show age-dependent hematopoietic defects including anemia, thrombocytopenia, and BM hypocellularity33
	Animals with heterozygous KO of Ddx41 function do not develop hematopoietic malignancies31, 32, 33	Patients with deleterious germ line DDX41 variants develop hematopoietic malignancies, mostly of myeloid lineage, with late onset1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,20,22, 23, 24
DDX41-interacting proteins	Spliceosomal components (C elegans)34	Spliceosomal components7
		R-loop–interacting proteins35,36
Alternative splicing changes in DDX41-mutant or knockdown cells	Increased alternative exon usage, intron retention, alternative 5' and 3' splice site usage (C elegans, zebrafish, mice)31,34,37	Increased exon inclusion and intron retention7
Mutual exclusivity with splicing mutations?	Yes. C elegans sacy-1 mutants show synthetic lethality with germ line splicing factor mutants34	Yes. Co-occurrence of somatic mutations in genes encoding splicing factors is rare, suggesting that DDX41's splicing function is critical7
Role in ribosome biogenesis (snoRNA and pre-rRNA processing)	Ddx41-deficient HSPCs display increased snoRNA levels33	Cells overexpressing DDX41 R525H display defects in pre-rRNA processing and had diminished cellular proliferation30
		DDX41-interacting RNAs are enriched for snoRNAs, suggesting that DDX41 could remove snoRNA-containing introns via splicing regulation33
R-loop interactions	Increased RNA:DNA hybrids result from insufficient Ddx41 levels, which induces a cGAS-STING-mediated inflammatory response that directs HSPC expansion (zebrafish)31	Increased RNA:DNA hybrids and consequently elevated dsDNA breaks result from insufficient DDX41 levels35
cGAS-STING interactions	Murine fetal liver Ddx41-null HSPCs display diminished inflammatory gene expression32	Loss of DDX41 in monocytic cells lowered dsDNA-triggered activation of the cGAS-STING pathway. However, expression of DDX41 R525H, with intact dsDNA binding but dampened helicase activity, activates the STING pathway38
		Human hematopoietic cells show paradoxical increased type I IFN signaling upon DDX41 knockdown35

BM, bone marrow; DDX41, DEAD-box helicase 41; KO, knockout.