Table 3.

Mouse models genetically engineered to express gene mutations encountered in patients with MDS or AML

Gene (reference)Mouse modelPhenotypeStrategy
DNMT3A & DNMT3B (14)Dnmt3a−/−, Dnmt3b−/−, and [Dnmt3a−/−, Dnmt3b−/−] straight KODnmt3a−/− died by 4 wk of age. Dnmt3b−/− are embryonic lethal. Dnmt3 double mutants severely impaired in de novo DNA methylation and died by E11.5Intercrossed Dnmt3a and Dnmt3b heterozygotes, which are grossly normal and fertile, to generate nulls
DNMT3A (19)Dnmt3afl/fl conditional KODnmt3a loss in HSCs leads to expansion of morphologically normal HSC with improper differentiationTransplantation of purified Mx1-Cre;Dnmt3afl/fl HSCs and deletion of Dnmt3a induced 4 weeks after transplanting
IDH1 (34)Idh1LSL/WT R132H conditional KIIncrease in hematopoietic progenitors, splenomegaly, and anemia with extramedullary hematopoiesisExpression of R132H mutation in all hematopoietic cells or specifically myeloid cells by crossing Idh1lsl/WT with VavCre or LysM-Cre, respectively
TET2 (29)Tet2f/f conditional KOBiallelic deletion of Tet2 results in progressive myeloproliferation, increase HSC self-renewal, CMML phenotypeDeletion of Tet2 in the hematopoietic compartments by crossing Tet2fl/fl mice with different tissue-specific Cre mice
EZH2 (50)Ezh2fl/fl conditional KOLoss of Ezh2 results in development of T-cell leukemia with almost complete penetrance in less than 1 year; implicates Ezh2 as a tumor suppressorEzh2fl/fl mice crossed with Mx-Cre Tg. Deletion of the set domain induced by poly(I)·poly(c) injections
EZH2 (54)Ezh2fl/fl conditional KO in a myeloid leukemia mouse modelIncreased numbers of differentiated leukemic cells leukemic and perturbed leukemic progression after Ezh2deletion suggesting Ezh2 is oncogenic in AMLTransplanted MLL-AF9–transformed GMPs from Cre-ERT;Ezh2fl/fl mice into lethally irradiated mice; deletion of Ezh2 by tamoxifen injections
ASXL1 (42)Asxl1tm1Bc/tm1Bc KOAsxl1 loss displays mild phenotype; differentiation defects of hematopoietic precursorsInsertion of a PGKneo cassette upstream from the PHD domain to disrupt Asxl1 expression globally.
ASXL1 (43)NRasG12D/Asxl1 shRNAAsxl1 loss causes myeloproliferation with myeloid infiltration in spleen and liver resulting in splenomegaly and hepatomegaly and impaired survivalTransplantation of bone marrow cells expressing NRasG12D in combination with Asxl1 short hairpin RNA construct or empty vector with GFP into lethally irradiated mice
SF3B1 (64)Sf3b1+/− mutantSf3b1 haploinsufficiency leads to various skeletal defects; homozygous null are embryonic lethalMutant allele generated by replacing 4 exons with neo gene to disrupt gene expression globally

Abbreviations: KO, knockout; KI, knockin.