Thymic Precursor Cells Generate Acute Myeloid Leukemia in NP23-NHD13 Double Transgenic Mice

Authors

• S Kundu
• E Park
• YJ Chung
• T Barlowe
• PD Aplan

Abstract

We previously generated mice that expressed either a NUP98–PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment. Both mice develop a wide variety of leukemia at 9-14 months of age. Surprisingly, 100% of the NP23-NHD13 mice developed acute myeloid leukemia (AML) within 3 months and were characterized by extraordinarily high WBC and replacement of the thymus with Mac1+/Gr1+ myeloid cells. The percent of malignant cells in the thymus was often higher than the bone marrow (BM); indicated that the AML in NP23-NHD13 mice arose in the thymus, as opposed to the BM. We transplanted double negative (DN) thymocytes from a NP23-NHD13 mouse invaded by AML cells to irradiated recipients. All mice developed AML within 26 days, indicating that the AML was aggressive and transplantable. We repeated the experiment, twice, using DN thymocytes from 4-5 wk non-leukemic mice. DN thymocytes again transmitted AML. Fractionating DN thymocytes into DN1-DN4 sub-populations revealed that AML initiating cells were found in the DN1 and DN2 compartments. DN thymocytes from non-leukemic mice were cultured on an OP9 stromal layer and showed markedly enhanced ability to differentiate into myeloid lineage cells compared to WT. The NP23-NHD13 cells lost expression of myeloid markers after 26 days; these cells were transplanted; all recipients were anemic, and demonstrated engraftment of NP23-NHD13 myeloid cells as well as a less prominent (8-38%) population of erythroid cells in the BM and spleen. These results demonstrate that NP23-NHD13 thymic progenitors retain myeloid and erythroid potential and are potently leukemogenic.

Scientific Focus Area: Cancer Biology

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