Table 1.

Clinical and biological characteristics of mutations in MDS

Biologic process	Genes	Type of mutation	Frequency	Effect on outcome in MDS patients	Normal biological function	Mutant biologic impact	Features of mouse model										Targeted downstream genes
							Model studied	White blood cells	Red blood cells	Platelets	HSCs and progenitors	HSC functions	MDS phenotype in mice	Period to onset	Other myeloid features	Competitive transplantations
Splicing	SF3B1	Missense, clustering the C-terminal HEAT domains (residues 622–781), with the most commonly mutated residue being K700	20–25%, (60–75% in RS-MDS)	Strong association with RS. Improved OS of SF3B1-mutant RARS patients compared with their wild-type counterparts.	Recognizes branching points of intron and adjusts 3′ splice site sp icing patterns	Increases aberrant 3′ splice site selection	Sf3b1K700E/+ Inducible knockin (Mx1-Cre) endogenous Sf3b1 locus (Obeng et al.)	No change	Macrocytic anemia	No change	LT-HSC↑ GMP↓	Decreased reconstitution in vivo	Dysplastic erythroid precursors without RS	64 weeks	No elevated blast, no leukemia	Impaired	ABCB7, PDS5A, PPP2R5A, MAP3K7
	SRSF2	Missense, clustering P95	8–12%	Mutations appear to cluster in MDS patients with RAEB or CMML and were found to be predictors for worsened OS	Recognizes ESE elements within pre-mRNA to promote exon recognition	Alters cassette exon splicing based on ESE sequence	Srsf2P95H/+X Inducible knockin (Mx1-Cre) endogenous Srsf2 locus (Kim et al.)	Leukopenia	Macrocytic anemia	No change	LT-HSC↑	Decreased reconstitution in vivo	Trilineage dysplasia	18 weeks	No leukemia (in up to 70 weeks)	Impaired	EZH2, CASP8
	U2AF1	Missense, clustering S34 and Q157	7–10%	Co-occurrs with ASXL1 mutations and were found to be predictors for worsened OS	Binds to the AG nucleotides near the 3′ splice cite in the intronic sequence	Alters 3′ splice acceptor sequence preference	U2af1S34f/+ Inducible knockin of S34F mutants U2AF1 (Mx1-Cre) Col1a1 locus (Shirai et al.)	Leukopenia	No change	No change	LT-HSC↑	Decreased reconstitution in vivo	No evidence of bone marrow dysplasia	4 weeks	No leukemia (in up to 52 weeks)	Impaired	H2AFY, EZH2, GNAS
	ZRSR2	Nonsense, frameshift	2–6%	Located on X chromosome and interacts with other prespliceosome components including the U2AF1/2 heterodimer and SRSF2	Required for efficient splicing of both the major (U2) and the minor (U12) class of introns	Produces aberrant retention of U12-type introns	No mouse models										WDR41, FRA10AC1
Chromatin modifications	EZH2	Nonsense, frameshift	3–7%	Co-occurring RUNX1 and STAG2 mutations. EZH2 mutations in MDS patients are associated with significantly worse prognosis, which is not due to AML transformation	Increases H3K27me3 as catalytic components of PRC2	Reduces H3K27me3	Ezh2Δ/Δ Inducible konckout (Cre- ERT)(Muto et al.)	Leukopenia	Anemia	Elevated	LT-HSC↑ MEP↑	N.A.	Myeloid dysplasia such as hyposegmentation	40 weeks	MDS/MPN like disease	N.A.	HMGA, PBX3, LMO1
	ASXL1	Nonsense, frameshift in C-terminal (exon 12)	15–20%	Co-occurring RUNX1 or STAG2 mutations. The mutation of ASXL1 predicted poor outcome in terms of response and OS after HMAs	Binds to EZH2 and increases globally H3K4me3 and H3K27me3 in specifically HOXA gene lesions. Removes H2AK119Ub due to cooperative BAP1	Reduces global H3K4me3 and H3K27me3 in HOX genes and H2AK119Ub	Asxl1E635RfsX15/+ conditional knockin (Vav- Cre) Rosa26 locus (Nagase et al.)	No change	Reduction in RBC	Elevated	LT-HSC↓ MEP↑	Decreased reconstitution in vivo	No evidence of bone marrow dysplasia	70 weeks	No leukemia (in up to 78 weeks)	Impaired	HOXA5/7/9, IRF8, BAP1
DNA methylation	TET2	Nonsense, frameshift, and missense in DSBH domain	20–25%	TET2 mutations do not appear to affect OS	Catalyzes conversion of 5- mc to 5-hmc	Tet2−/− conditional knockout (Li et al.)	Leukocytosis (monocytosis)	Reduction in RBC	No change	LT-HSC↓ GMP↑	Increased reconstitution in vitro colony formation capacity	Monocytosis, MDS/MPN features	16 weeks	TET2 −/− (33%), TET2 +/− (8%) died within 1 year because of CMML-like diseases	Impaired	Concurrent depletion of EZH2 and TET2, or ASXL1 and TET2 establishes more advanced MDS phenotypes
	DNMT3A	Missense, clustering exon 23 with the most commonly mutated R882 residues	8–12%	DNMT3A mutations do not appear to affect OS	Catalyzes conversion of 5- cytosine to 5-mc	Reduces 5-mc	Dnmt3aR882H/+ Inducible knockin (Mx1-Cre) endogenous Dnmt3a locus (Guryanova et al.)	No change	No change	No change	LT-HSC↑	Increased reconstitution in vitro colony formation capacity	No evidence of bone marrow dysplasia	40 weeks	No leukemia	N.A.	Cooperated with FLT3- ITD and NPM1 mutations to induce AML in vivo
	IDH1/2	Missense, clustering R132 (IDH1), R140, and R172 (IDH2)	1–4% (IDH1) 2–5% (IDH2)	Mutations in IDH1R132 and the analogous IDH2R172 mutations are possibly associated with adverse OS in MDS.	Catalyzes the oxidative decarboxylation of isocitrate to α-KG and carbon dioxide	Produces 2– HG, which serves as a competitive inhibitor of α– KG–dependent enzymes, including the TET family of enzymes and the Jumonji family of histone lysine demethylases	Idh2R140Q/+ Inducible knockin Rosa26 locus (Kats et al.)	No change	No change	No change	LT-HSC↑	Block of erythroid differentiation	No evidence of bone marrow dysplasia	28 weeks	No leukemia	No differences	IDH2 and FLT3-ITD cooperate in leukemia initiation

RS-MDS ring sideroblasts-myelodysplastic syndromes, RARS refractory-anemia with RS, OS Overall survival, N.A. not available, H3K4me3 histone 3 at lysing 4 trimethylation, H3K27me3 histone 3 at lysing 27 trimethylation, H2AK119Ub ubiquitination at lysine 119 of histone H2A, DSBH double-stranded β-helix, MML chronic myelomonocytic leukemia, LT-HSC long-term hematopoietic stem cell, GMP granulocyte myeloid progenitor, AG adenine Guanine dinucleotides, ESE exonic splice enhancer, 2- HG 2-hydroxyglutarate, α-KG alpha-Ketoglutaric acid