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 7

Ablation of Kdm2b accelerates KRAS-driven myeloid transformation.

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Ablation of Kdm2b accelerates KRAS-driven myeloid transformation. (A) Ka...
(A) Kaplan-Meier plots show the survival of AML patients in the TCGA LAML cohort that express low and high levels of KDM2B (left) and EZH2 (right). Survival analysis was performed with the PRECOG profiles software. (B) Kaplan-Meier plot showing the survival of Vav1-Cre KrasG12D Kdm2b+/+ (solid line) and Vav1-Cre KrasG12D Kdm2bfl/fl (dotted line) mice. Median survival in brackets. (C) Scatter plot of wbc and stacked bar graph of percentage contribution of different lineages. P < 0.05, ANOVA. Red dotted line indicates the maximum physiological range. Bottom: flow cytometry analysis showing the frequency (%) of T, B, and myeloid cells in the peripheral blood. (D) May-Grünwald Giemsa staining of blood smears and BM cytospin preparations from 3- and 6-week-old mice. Black arrows, lymphocytes; red arrows, immature granulocytes; orange arrows, myeloblasts. Scale bars: 10 μm. (E) RNA was isolated from Linneg Vav1-Cre KrasG12D Kdm2b+/+ and Kdm2bfl/fl cells (n = 2 mice for each genotype), 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-null KRAS-driven leukemias. Regulators with z scores greater than 2 and P overlap values of less than 0.01 are shown.