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J.N. Fisher et al.
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Figure 1. Expression of iNUP98-KMT2A leads to development of a myelodysplastic syndrome-like disease in transgenic mice. (A) iNUP98-KMT2A mice contain a reverse Tet transactivator (rtTA) element in the Rosa26 gene locus on chromosome 6 (Chr 6), and a human NUP98-KMT2A open reading frame after a TET-responsive element (TRE) in the Hprt locus on the X-chromosome (Chr X). Administration of the tetracycline analog, doxycycline (DOX) leads to expression of the NUP98-KMT2A fusion construct. (B) Kaplan-Meier curves for DOX-exposed primary-induced adult (6-10 weeks) iNUP98-KMT2A mice and wildtype (WT) littermates (CTRL), as well as adult WT irradiated recipients of iNUP98-KMT2A total bone marrow transplants (BMT) exposed to DOX (BMT + DOX) and BMT recipients taken off DOX (BMT DOX rem) after 31 weeks. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001, log-rank test. (C) Blood values from DOX-exposed adult iNUP98-KMT2A mice and WT littermates (CTRL), as well as adult WT irradiated recipients of iNUP98-KMT2A total BMT exposed to DOX (BMT + DOX) and BMT recipients taken off DOX (BMT DOX rem) after 31 weeks. *P<0.05, **P<0.01, ***P<0.001, unpaired t-tests. WBC: white blood cells; RBC: red blood cells; HGB: hemoglobin; LUC: abnormal leukocytes. (D) Dysplastic immature myeloid cells on peripheral blood smears of pre-leukemic DOX-induced iNUP98-KMT2A mice as well as WT recipients of iNUP98-KMT2A total BMT on DOX. Scale bar: 10 μm. (E) Histopathology sections of DOX-exposed iNUP98-KMT2A mice show extramedullary hematopoiesis in the spleen and liver. Scale bar: 100 μm. (F) Immunophenotype (Mac- 1, Gr-1, FcyRII/III and c-Kit, given in %) of total bone marrow cells from pre-leukemic iNUP98-KMT2A mice. The flow plots are representative of three mice/group. (G) Immunophenotype (Mac-1, Gr-1, FcyRII/III and c-Kit, given in %) of total bone marrow cells from WT mice transplanted with iNUP98-KMT2A bone marrow on DOX. Mice exhibited two diverse phenotypes; denoted a and b. Transplanted mice off DOX were used as the negative control.
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haematologica | 2020; 105(7)