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Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.

ABSTRACT: Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic myeloblasts. The marked infiltration of thymus led to the intriguing hypothesis that AML generated in NP23-NHD13 mice arose in the thymus, as opposed to the bone marrow (BM). Transplantation of CD4-CD8- double negative (DN) thymocytes (which were also negative for Mac1 and Gr1) from leukemic NHD13/NP23 mice demonstrated that DN thymocytes could transmit AML, and limiting dilution studies showed that leukemia initiating cells were increased 14-fold in the thymus compared to BM. Further thymocyte fractionation demonstrated that DN1 and DN2, but not DN3 or DN4 fractions transmitted AML, and a marked expansion (100-fold) of Lineage-Sca1?+?Kit?+?(LSK) cells in the thymus of the NP23-NHD13 mice. Taken together, these results show that the thymus of NP23-NHD13 mice acts as a reservoir for AML initiating cells and that thymic progenitors can transmit AML.

SUBMITTER: Kundu S

PROVIDER: S-EPMC6868234 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.

Kundu Subhadip S Park Eun Sil ES Chung Yang Jo YJ Walker Robert L RL Zhu Yuelin J YJ Negi Vijay V Meltzer Paul S PS Aplan Peter D PD

Scientific reports 20191120 1

Transgenic mice that express either a NUP98-PHF23 (NP23) or NUP98-HOXD13 (NHD13) fusion in the hematopoietic compartment develop a wide spectrum of leukemias, including myeloid, erythroid, megakaryocytic and lymphoid, at age 9-14 months. NP23-NHD13 double transgenic mice were generated by interbreeding NP23 and NHD13 mice. Remarkably, 100% of the NP23-NHD13 double transgenic mice developed acute myeloid leukemia (AML) within three months, characterized by replacement of the thymus with leukemic ...[more]

PMID: 31748606

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Project description:B-1 and B-2 lymphocytes are derived from distinct developmental pathways, and represent layered arms of the innate and adaptive immune systems, respectively. In contrast to the majority of murine B- cell malignancies, which stain positive with the B220 antibody, we discovered a novel form of B-cell leukemia in NUP98-PHF23 (NP23) transgenic mice. The immunophenotype (Lin- B220 - CD19+ AA4.1+) was identical to B-1 progenitor cells, and VH gene usage was skewed toward 3’ V regions, similar to murine fetal liver B-cells. We performed RNA sequencing and determined that the expression profile of these leukemias was most similar to fetal liver pro B fraction BC, a known source of B-1 B cells, further supporting a B-1 progenitor origin of these leukemias. The NP23 B-1 progenitor ALLs acquired spontaneous mutations in both Bcor and Jak pathway (Jak1/2/3 and Stat5a) genes, supporting a hypothesis that mutations in three critical pathways (stem cell self-renewal, B-cell differentiation, and cytokine signaling) collaborate to induce B-cell precursor (BCP) ALL. Finally, the Tslp cytokine is required for murine B- 1 development, and chromosomal rearrangements resulting in overexpression of the TSLP receptor (CRLF2) are present in some high risk BCP ALL patients (referred to as CRLF2r ALL). Gene expression profiles of NP23 pro-B1 ALL were more similar to CRLF2r ALL than non-CRLF2r ALL, and analysis of VH gene usage from CRLF2r ALL patients demonstrated preferential usage of VH regions used by human B-1 B-cells, leading to the suggestion that this subset of BCP ALL patients have a malignancy of B-1, rather than B-2 B-cell origin. RNA was extracted from seven NP23 pro-B1, two E2A-PBX pre-B2, and three Eμ-RET pre-B2 ALL samples, and purified wild-type fetal liver Ter119-AA4.1+CD19+B220+ cells pooled from E15.5-16 embryos. Cells were purified using fluorescence activated cell sorting (FACS) at the NCI FACS core facility using an Aria Violet-Cli FACS sorter. RNA samples were prepared using TRIzol reagent (Invitrogen) following the manufacturer’s recommended protocol. Samples were evaluated using Fragment Analyzer and NanoDrop. Indexed cDNA sequencing libraries were prepared using the TruSeq Stranded mRNA Sample Preparation Kit, and bar-coded with individual tags, following the manufactures recommendations. Library preparation was performed using a 96-well plate method. The libraries were quantified using Qubit fluoroscopy and the NGS kit for Fragment Analyzer. Any failed results from the fragment analyzer were repeated using 2100 Bioanalyzer. Indexed libraries were prepared as equimolar pools and run on HiSeq4000 (2x150 paired end runs) to generate 40 million paired-end reads per sample library.

Dataset Information

Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.

Publications

Thymic precursor cells generate acute myeloid leukemia in NUP98-PHF23/NUP98-HOXD13 double transgenic mice.

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