Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis
Jaclyn Andricovich, … , Adlen Foudi, Alexandros Tzatsos
Jaclyn Andricovich, … , Adlen Foudi, Alexandros Tzatsos
Published January 25, 2016
Citation Information: J Clin Invest. 2016;126(3):905-920. https://doi.org/10.1172/JCI84014.
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Research Article Hematology

Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis

Abstract

The development of the hematopoietic system is a dynamic process that is controlled by the interplay between transcriptional and epigenetic networks to determine cellular identity. These networks are critical for lineage specification and are frequently dysregulated in leukemias. Here, we identified histone demethylase KDM2B as a critical regulator of definitive hematopoiesis and lineage commitment of murine hematopoietic stem and progenitor cells (HSPCs). RNA sequencing of Kdm2b-null HSPCs and genome-wide ChIP studies in human leukemias revealed that KDM2B cooperates with polycomb and trithorax complexes to regulate differentiation, lineage choice, cytokine signaling, and cell cycle. Furthermore, we demonstrated that KDM2B exhibits a dichotomous role in hematopoietic malignancies. Specifically, we determined that KDM2B maintains lymphoid leukemias, but restrains RAS-driven myeloid transformation. Our study reveals that KDM2B is an important mediator of hematopoietic cell development and has opposing roles in tumor progression that are dependent on cellular context.

Authors

Jaclyn Andricovich, Yan Kai, Weiqun Peng, Adlen Foudi, Alexandros Tzatsos

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Figure 3

Ectopic expression of KDM2B expands lymphoid-primed progenitors in a Jumonji domain–dependent manner.

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Ectopic expression of KDM2B expands lymphoid-primed progenitors in a Jum...
(A) Schematic of doxycycline-inducible Kdm2b or Kdm2bΔJmjC mice. Crosses with Vav1-Cre removed the “lox-stop-lox” cassette and allowed the expression of rtTA and GFP in the hematopoietic system, which was confirmed by flow cytometry. Bottom: Linneg BM cells were isolated from the indicated mice and cultured in the presence of doxycycline for 3 days. Ectopic expression of KDM2B was confirmed by Western blotting probing with an anti-MYC antibody that recognizes the exogenous MYC-tagged protein. (B) Composite analysis showing the frequency (%) of lymphoid (gate B for LMPP and gate C for CLP) and myeloid (gate A for MEP, CMP, and GMP) progenitors in mice that were administered doxycycline for 9 to 12 weeks to express KDM2B or KDM2BΔJmjC. Bold red type denotes the gates, and black numbers denote the percentages of gated cells. Bar graphs show the contribution (%) of GMPs, CMPs, MEPs, CLPs, LMPPs, and LT-HSCs in BM. *P < 0.05, ANOVA. (C) Scatter plot showing the frequency (%) of T, B, and myeloid cells in doxycycline-treated mice of the indicated genotypes. *P < 0.05, ANOVA. NS, not significant.