Insights into myelodysplastic syndromes from current preclinical models

Table 1 Bethesda diagnostic criteria for myeloid dysplasia in mice

(1) At least one of the following

A: Neutropenia

B: Thrombocytopenia (without leucocytosis or erythrocytosis)

C: Anemia (without leucocytosis or thrombocytosis)

(2) Maturation defect in myeloid cells manifest as at least one of

A: Dysgranulopoiesis, dyserythropoiesis, or dysplastic megakaryocytes with or without increased myeloid immature forms or blasts

B: At least 20% myeloid immature forms or blasts

(3) Disorder is not AML

Subclassification

Myelodysplastic syndrome if meeting criteria (2)A

Cytopenia with increased blasts if meeting (2)B

Summarised from Kogan et al[60]. AML: Acute myeloid leukemia.

Table 2 Candidate genes used to model myelodysplastic syndromes in mice and their correlation to human myelodysplastic syndromes

Gene(s) studied	Chromosomal location	Frequency in human MDS	Equivalent human MDS subtype according to WHO 2008 classification	Ref.
Transcription factors
NUP98-HOXD13	t(2;11)(q31;p15)	Rare	RCMD	[69]
RUNX1	21q22.3	15%-40%	RAEB	[105]
EVI1	3q26.2	Rare	RCMD	[136]
SALL4	20q13.2	15%-40%	RCMD	[139]
NPM1	5q35.1	About 4%	RCMD	[138]
Signalling molecules
NRAS	1p13.2	About 20%	RAEB	[142]
BCL2	18q21.33	Unknown
PTEN	10q23.3	Unknown	RCMD	[140]
SHIP	2q37.1	Unknown
Epigenetic regulators
TET2	4q24	20%-30%	RCMD/CMML	[115]
ASXL1	20q11.21	15%-20%	RCMD	[122,123]
EZH2	7q36.1	2%-6%	RCMD/MPN	[141]
MLL5	7q22.1	Unknown	No definitive MDS	[145]
RNA spliceosome
SRSF2	17q25.2	15%-30%	RCMD	[98]
U2AF1	21q22.3	11%	No definitive MDS	[100]
SF3B1	2q33.1	10%-20%	RARS, RARS-T	[101]
Telomere function
TERT	5p15.33	Unknown	RCMD	[124]
5q-
RPS14	5q33.1	About 10%	5q-like	[91]
CD74-SMIM3 (NID67)	5q32-q33.1			[92]
SPARC	5q33.1			[97]
MIR145/146A	5q32-34			[143]
APC	5q22.2			[99]
CSNK1A1	5q32			[94]

WHO: World Health Organization; RARS: Refractory anemia with ringed sideroblasts; RARS-T: Refractory anemia with ringed sideroblasts and thrombocytosis; RCMD: Refractory anemia with multilineage dysplasia; RAEB: Refractory anemia with excess blasts; MPN: Myeloproliferative neoplasm; MDS: Myelodysplastic syndromes; CMML: Chronic myelomonocytic leukemia.

Table 3 Published mouse models of myelodysplastic syndromes

Gene(s) studied	Model/technique	Tractability to human MDS								Ref.
		Anemia	Multi-lineage cytopenias	Dysplasia	Bone marrow cellularity	HSPC skewing	Secondary leukemia	Latency to leukemia	Survival
NUP98-HOXD13	Transgenic	Yes	Yes	Yes	Hyper-	Yes	Yes2	14 mo	-	[69]
Cd74-Nid67	Large scale chromosomal deletion, RPS14 haploinsufficient	Yes	No	Yes	Hypo-	Yes	No	-	1	[92]
SPARC	Knock-out	No	No	Yes	1	1	No	-	1	[97]
MIR-145, MIR146a	Retroviral transduction	No	No	Yes	1	1	Yes	4-14 mo	-	[143]
APC	Transgenic, haploinsufficient	Yes	No	Yes	1	Yes	No	-	3-8 mo	[99]
Csnk1a1	Transgenic, inducible	Yes	Yes	Yes	Yes	Yes	No	-	1	[94]
Srsf2	Transgenic, inducible	Yes	Yes	Yes	Normal	Yes	No	-	1	[98]
U2af1	Transgenic, inducible	No	No	No	Normal	Yes	No	-	-	[100]
Sf3b1	Transgenic, haploinsufficient	Yes	No	Yes	1	1	No	-	About 12 mo	[101]
RUNX1-D171N	Retroviral transduction	Yes	Yes	Yes	Normal to hyper-	1	Yes	4-13 mo	-	[105]
RUNX1-S291fsX300	Retroviral transduction	Yes	Yes	Yes	Normal to hyper-	1	Yes	4-13 mo	-	[105]
RUNX1S291fs/Ezh2	Retroviral transduction	Yes	Yes	Yes	Variable	1	No	-	262 d	[125]
Tet2	Transgenic, hypomorphic	Yes	Yes	Yes	Hyper-	Yes	No	-	11 mo	[115]
Tet2/Ezh2	Transgenic, inducible	Yes	Yes	Yes	Hyper-	Yes	No	-	10 mo	[141]
ASXL1	Transgenic, inducible	Yes	Yes	Yes	Hypo-	Yes	No	-	Median 50 wk	[122]
Asxl1	Transgenic, constitutive	Yes	Yes	Yes	Normal to hyper-	Yes3	16 mo	8-42 d	-	[123]
TERT	Transgenic, inducible	Yes	Yes	Yes	Hyper	Yes	Yes	1	12 mo	[124]
Evi1	Retroviral transduction	Yes	Yes	Yes	Hyper-	1	No	-	10-12 mo	[136]
SALL4	Transgenic	Yes	Yes	Yes	Hyper-	Yes	Yes	6 wk to 12 mo	-	[139]
Npm1	Transgenic, haploinsufficient	No	No	Yes	Hyper	No	Yes	24 mo	-	[138]
NRASD12-BCL2	Transgenic, inducible/constitutive	1	No	Yes	1	Yes	Yes	3-6 mo	-	[142]
Pten/Ship	Transgenic, Pten +/- Ship -/-	Yes	Yes	1	Hypo	Yes	No	-	5 wk	[140]
Dido	Knock-out	Yes	No	Yes	1	1	No	-	1	[137]
Arid4a	Knock-out	Yes	Yes	Yes	Hyper-	1	Yes	5 mo	-	[144]
Mll5	Knock-out	Yes	No	No	1	1	No	-	-	[145]

¹Denotes not reported, denotes not applicable;

²Some mice developed pre-T cell acute lymphoblastic leukemia;

³Only 1 of 18 mice developed AML. HSPC: Hematopoietic stem and progenitor cells; MDS: Myelodysplastic syndromes; AML: Acute myeloid leukemia.