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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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 2

KDM2B is required for maintenance and lineage commitment of HSPCs.

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KDM2B is required for maintenance and lineage commitment of HSPCs. (A) F...
(A) Flow cytometric analysis of Vav1-Cre (left) and Mx1-Cre mice 2 months after pIpC (right) showing LinnegKS+ and LT-HSC frequencies (%) in BM of 10- to 15-week-old WT and Kdm2b-null mice. Bar graphs show mean ± SEM. *P < 0.05; **P < 0.01. (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. Bold red type denotes the gates, and black numbers denote the percentages of gated cells. Right: bar graphs show the contribution (%) of LMPPs and CLPs in BM. Bottom: bar graphs depicting the percentages of LinnegK+S– cells and the frequency (%) of GMP, CMP and MEP in BM. *P < 0.05; **P < 0.01. (C) May-Grünwald Giemsa–stained cytospin preparations of WT and Kdm2b-null BM. Note the rarity of lymphocytes (black arrows) and the expansion of immature myeloid cells (red arrows) in Kdm2b-null BM. Scale bars: 10 μm. (D) Top: scatter plots of wbc counts. Red dotted line indicates minimum physiological range. Bar graphs show the absolute number of lymphocytes (LYM), monocytes (MONO), granulocytes (GRAN), platelets (PLT), and rbc. Bottom: representative flow cytometric analysis and cumulative scatter plot showing the frequency (%) of T, B, and myeloid (M) cells in the peripheral blood. *P < 0.05. NS, not significant.