Mouse model | HSC phenotype | Disease phenotype | Disease type | Histone modification | References |
---|---|---|---|---|---|
Asxl1−/− | Decreased LSK | Dysplastic neutrophils, multiple lineage cytopenias | MDS-like disease, MDS/MPN | Decreased H3K27me3, H3K4me3 | [71] |
Asxl1fl/fl Mx1 Cre or Vav Cre | Increased LT-HSC and LSK | Cytopenias (i.e., leukopenia and anemia), erythroid dysplasia | MDS-like disease | Decreased H3K27me3 | [70] |
Asxl1+/−;Nf1+/− | Increased LT-HSCs | Hepatosplenomegaly, leukocytosis, anemia, thrombocytopenia, disrupted architecture, and myeloid infiltration of spleen and liver | MDS, MDS/MPN, myeloid leukemia | Increased H3K4me3 | [64] |
JAK2V617F;Asxl1+/− | Increased short-term ST- HSC and MEP, and decreased MPP | Leukocytosis and thrombocytosis, megakaryocytic proliferation, increased marrow and splenic erythroid precursors, disrupted splenic architecture, and myeloid infiltration | Accelerated development of MPN, and progression to myelofibrosis and sAML | Not evaluated | [69] |
Asxl1-MT (sublethally irradiated mice transplanted with bone marrow cells harboring an Asxl1 mutation mimicking ASXL1 G646WfsX12) | Not evaluated | Multilineage myelodysplasia, pancytopenia | MDS-like disease, occasional progression to AML | Decreased H3K27me3 | [55] |
Asxl1tm/+  + MN1 (mimicking ASXL1 G646WfsX12) | Promoted stem cell activities in MN1 overexpression background (i.e., increased long-term colony-forming cells) | facilitates engraftment of cells overexpressing MN1 | None observed | Increased H3K27me3 with attenuated correlation between H3K27me3 and gene down-regulation | [62] |
Asxl1G643fs/+ (heterozygous knock-in of Asxl1 mutant G643WfsX12 mimicking ASXL1G646fs) | Decreased LT-HSC, LSK, MP, CMP, GMP and MEP | Leukocytosis, anemia, thrombocytosis, myeloid dysplasia in the BM, splenomegaly, disrupted splenic architecture, myeloid, and perivascular infiltration in liver | Recapitulates human low-risk MDS with some mice developing MDS/MPN-like disease after a long latency | Decreased H2AK119Ub | [72] |
Asxl1-MT KI (Asxl1 mutant knock-in mimicking ASXL1 E635RfsX15) | Decreased LSK, LT-HSCs and MPP, and increased MEPs | Mild leukopenia, and anemia, thrombocytosis, hypocellular bone marrow, myeloid skewing | CHIP | Decreased H3K4me3, H2AK119Ub, H3K27me3 | |
Asxl1Y588XTg (Vav1 promoter-driven Flag-Asxl1Y588X transgenic) | Increased ST-HSC and LSK, increased GMP, and decreased CMP | Hepatosplenomegaly, myeloid sarcoma, myeloid infiltration | Myeloid leukemia, MPN, MDS, MDS/MPN | Increased H3K122Ac and H3K27Ac, and alters H2AK119Ub1 occupancy at promoters of Hoxa genes | [75] |
Bap1Δ/+; Asxl1Y588XTg | Normalization of GMP and CMP | Normalization of spleen size | Prevented the development of myeloid malignancies | Partially restored H2AK119Ub1 occupancy at promoters of Hoxa genes | [76] |
Asxl2−/− | Increased HSC and LSK | Pancytopenia, splenomegaly, disrupted splenic architecture, myeloid infiltration in spleen | MDS-like disease | Increased or decreased signals (> 1000 regions) for H3K27ac, H3K4me1, or H3K4me2 | [77] |
Asxl2fl/fl Mx1 Cre | Decreased HSC and LSK | Granulocytic and erythroid dysplasia, leukopenia, thrombocytopenia, | MDS-like disease | Increased H3K27Ac, H3K4me1 | [61] |