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p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia
Na Man, … , Maria E. Figueroa, Stephen D. Nimer
Na Man, … , Maria E. Figueroa, Stephen D. Nimer
Published October 8, 2021
Citation Information: JCI Insight. 2021;6(19):e138478. https://doi.org/10.1172/jci.insight.138478.
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Research Article Hematology

p300 suppresses the transition of myelodysplastic syndromes to acute myeloid leukemia

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Abstract

Myelodysplastic syndromes (MDS) are hematopoietic stem and progenitor cell (HSPC) malignancies characterized by ineffective hematopoiesis and an increased risk of leukemia transformation. Epigenetic regulators are recurrently mutated in MDS, directly implicating epigenetic dysregulation in MDS pathogenesis. Here, we identified a tumor suppressor role of the acetyltransferase p300 in clinically relevant MDS models driven by mutations in the epigenetic regulators TET2, ASXL1, and SRSF2. The loss of p300 enhanced the proliferation and self-renewal capacity of Tet2-deficient HSPCs, resulting in an increased HSPC pool and leukemogenicity in primary and transplantation mouse models. Mechanistically, the loss of p300 in Tet2-deficient HSPCs altered enhancer accessibility and the expression of genes associated with differentiation, proliferation, and leukemia development. Particularly, p300 loss led to an increased expression of Myb, and the depletion of Myb attenuated the proliferation of HSPCs and improved the survival of leukemia-bearing mice. Additionally, we show that chemical inhibition of p300 acetyltransferase activity phenocopied Ep300 deletion in Tet2-deficient HSPCs, whereas activation of p300 activity with a small molecule impaired the self-renewal and leukemogenicity of Tet2-deficient cells. This suggests a potential therapeutic application of p300 activators in the treatment of MDS with TET2 inactivating mutations.

Authors

Na Man, Gloria Mas, Daniel L. Karl, Jun Sun, Fan Liu, Qin Yang, Miguel Torres-Martin, Hidehiro Itonaga, Concepcion Martinez, Shi Chen, Ye Xu, Stephanie Duffort, Pierre-Jacques Hamard, Chuan Chen, Beth E. Zucconi, Luisa Cimmino, Feng-Chun Yang, Mingjiang Xu, Philip A. Cole, Maria E. Figueroa, Stephen D. Nimer

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Figure 1

Loss of p300 in Tet2-deficient mice accelerates the onset of leukemia and shortens survival.

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Loss of p300 in Tet2-deficient mice accelerates the onset of leukemia an...
(A) Kaplan-Meier survival curve of mice after poly(I:C) injections for each genotype (WT, Ep300Δ/Δ, Tet2+/–, Ep300Δ/ΔTet2+/–, Tet2–/–, and Ep300Δ/ΔTet2–/–). Loss of p300 in Tet2-deficient mice shortens the survival time. (B) WBC counts in peripheral blood of endpoint Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice and age-matched Tet2+/– and Tet2–/– mice. The WT, Ep300Δ/Δ, and Tet2–/– mice were age-matched to Ep300Δ/ΔTet2–/– mice and Tet2+/– mice were age-matched to Ep300Δ/ΔTet2+/– mice. (C) Splenomegaly and granulocytic sarcoma found in Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice at endpoint, compared with age-matched WT, Tet2–/–, and Tet2+/– mice. (D) Morphology of peripheral blood and bone marrow cells and histology of spleen from moribund Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice. Scale bar for peripheral blood and bone marrow cells is 10 μm and for spleen is 50 μm. (E and F) Representative flow cytometry profiles (E) and percentage of c-Kit+ cells in the bone marrow (F) of moribund Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice and age-matched Tet2+/– and Tet2–/– mice. (G) Percentage of LSK cells in the Lin– bone marrow cells of moribund Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice and age-matched Tet2+/– and Tet2–/– mice. (H) Percentage of Mac-1+ cells in the bone marrow of moribund Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice and age-matched Tet2+/– and Tet2–/– mice. (I) Percentage of B220+ cells in the bone marrow of moribund Ep300Δ/ΔTet2+/– and Ep300Δ/ΔTet2–/– mice and age-matched Tet2+/– and Tet2–/– mice. (J) Kaplan-Meier survival curve after poly(I:C) injections for each genotype (WT, Ep300Δ/Δ, Tet2+/–, Ep300Δ/ΔTet2+/–, Tet2–/–, and Ep300Δ/ΔTet2–/–) in transplantation models. P values were determined using a 2-tailed Student’s t test for samples of unequal variance. LSK, lineage– Sca1+c-Kit+.

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