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 8

Ectopic expression of KDM2B antagonizes KRAS-driven myeloid transformation.

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Ectopic expression of KDM2B antagonizes KRAS-driven myeloid transformati...
(A) Left: scatter plot of wbc in Vav1-Cre KrasG12D Tet-Kdm2b and Tet-Kdm2bΔJmjC mice. P < 0.05, ANOVA. Red dotted line indicates the maximum physiological range. Right: stacked bar graph shows the contribution (%) of granulocytes, monocytes, and lymphocytes after doxycycline administration. (B) Kaplan-Meier plot showing the survival of Vav1-Cre KrasG12D Tet-Kdm2b and Tet-Kdm2bΔJmjC mice. n = 5; median survival in brackets. (C) RNA was isolated from Linneg Vav1-Cre KrasG12D Tet- and Vav1-Cre KrasG12D Tet-Kdm2b cells (n = 2 mice), and gene-expression profiles were obtained with the MoGene 2.0 ST whole transcript (exon) microarray (Affymetrix). Bar graph shows IPA of the differentially expressed genes (P < 0.05 and fold change > 1.4). The x axis (log scale) corresponds to the binomial raw P values. Bottom: ingenuity regulator analysis (see Methods) in KDM2B-overexpressing KRAS-driven leukemias. Regulators with z scores greater than 2 and P overlap values of less than 0.01 are shown.