(A) Representative H&E staining of tissue sections from IDH2R140Q–t;Flt3ITD compound transgenic animals and an Flt3ITD control animal. Compound transgenic animals develop acute myeloid (AML-like) and lymphoid (ALL-like) malignancies whereasFlt3ITD animals develop myeloproliferative disease (MPD). Left panels: a compound transgenic animal diagnosed with AML-like disease. Apoptotic debris and numerous tingible body macrophages (magnified in inset, upper left panel) characteristic of highly proliferative disease are evident throughout. Infiltration of intermediate-sized blast-like immature mononuclear cells (magnified in inset, upper right panel) is evident in the red pulp of the spleen, the liver, and kidney. Middle panels: a compound transgenic animal diagnosed with ALL-like disease. T lymphoblasts (confirmed by immunohistochemical staining using anti-CD3ε antibody, not shown) with high-grade morphology are present in the thymus, spleen, liver, and lung. Numerous mitoses are present, characteristic of a rapidly proliferative disease. Right panels: MPD in an Flt3ITD animal with a hypercellular bone marrow with myeloid maturation and increased myeloid cells in the spleen. Original magnification, 600×.
(B) Examples of FACS plots demonstrating the types of acute leukemia diagnosed in IDH2R140Q–t;Flt3ITD compound transgenic animals. Left panels: presence of CD3ε+cKit+ lymphoblasts in the thymus and bone marrow; cells in the thymus are exclusively CD8+CD4−. Right panels: cells in the bone marrow are almost exclusively Mac1+/low and a population of Mac1lowcKit+ immature cells is evident; in the thymus of the same animal, CD3ε−CD8+ lymphoblasts are present.
(C and D) Primary AML (BM MNCs from donor #5517) and ALL (thymocytes from donor #12063) cells recapitulate a lethal leukemia in transplanted recipients treated with doxycycline. FACS plots demonstrate the overwhelming majority of donor-derived (CD45.2+) cells in the bone marrow of moribund recipients and the loss of lineage markers (Mac1 and CD3ε, respectively) upon serial transplantation.
See also .