Histone demethylase KDM2B regulates lineage commitment in normal and malignant hematopoiesis
Jaclyn Andricovich, Yan Kai, Weiqun Peng, Adlen Foudi, Alexandros Tzatsos
Jaclyn Andricovich, Yan Kai, Weiqun Peng, Adlen Foudi, Alexandros Tzatsos
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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 5

KDM2B regulates cell fate and cycling of HSPCs.

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KDM2B regulates cell fate and cycling of HSPCs. (A) Volcano plot shows t...
(A) Volcano plot shows the differentially expressed genes (P < 0.05 and fold difference > 1.5) in Kdm2b-null LinnegKS+ progenitors compared with WT (n = 2). Red circles highlight the position of the indicated transcripts. Right: bar graph (mean ± SD) shows fold difference of the indicated transcripts in LinnegKS+ by qRT-PCR. (B) Bar graph (mean ± SD) shows the fold difference determined by qRT-PCR in the expression of the indicated transcripts in Kdm2b-null (black bars) and KDM2B-overexpressing (OE, gray bars) Linneg cells compared with WT controls. (C) Intracellular flow cytometric analysis of IKAROS and PAX5 transcription factors in WT and Kdm2b-null Linneg BM. (D) IPA of the differentially expressed genes identified in A. The x axis (log scale) corresponds to the binomial raw P values. (E) GSEA leading edge analysis identified 3 distinct modules regulated by KDM2B in LinnegKS+ cells. Color bar shows the overlap (%) between the individual gene sets. (F) Cell-cycle analysis of LinnegKS+ cells. n = 2. *P < 0.05.