These Mll-CbpSTOP mice carry a floxed STOP cassette upstream of exon 8 of the myeloid/lymphoid or mixed-lineage leukemia 1 (Mll1) gene, and a CREB binding protein (Cbp) cDNA, a Simian virus 40 polyadenylation signal (SV40 pA), and a puromycin resistance sequence (puro) in Mll1 exon 8. Mice that are heterozygous for the targeted mutation are viable and fertile with no Mll-Cbp fusion protein expression detected. Homozygous mice are not viable. The MLL-CBP fusion protein is a characteristic of the t(11;16)(q23;p13) chromosomal translocation found in patients with therapy-induced myeloproliferative diseases, including acute myelomonocytic leukemia (t-AMML), chronic myelomonocytic leukemia (t-CMML), and myelodysplastic syndrome (t-MDS).
When bred to mice that express interferon-inducible Cre recombinase (see Stock No. 003556), resulting offspring treated with polyinosinic-polycytidylic acid (pI-pC) will have the floxed-STOP cassette deleted in the cre-expressing tissues. This allows the expression of the MLL-CBP in cre-expressing tissue. These mice exhibit a three-fold reduction in common lymphoid progenitors (CLPs) and a 3-fold increase in myeloid progenitors, with enhanced proliferation, in bone marrow. This myeloid hyperplasia is evident within days of MLL-CBP expression. Subsequent γ-irradiation or N-ethyl-N-nitrosourea (ENU) treatment results in the onset of a spectrum of myeloproliferative disease and decreased survival.
