Differential redox-regulation and mitochondrial dynamics in normal and leukemic hematopoietic stem cells: A potential window for leukemia therapy.

The prognosis for many patients with acute myeloid leukemia (AML) is poor, mainly due to disease relapse driven by leukemia stem cells (LSCs). Recent studies have highlighted the unique metabolic properties of LSCs, which might represent opportunities for LSC-selective targeting. LSCs characteristically have low levels of reactive oxygen species (ROS), which apparently result from a combination of low mitochondrial activity and high activity of ROS-removing pathways such as autophagy.

Transcriptional regulators CITED2 and PU.1 cooperate in maintaining hematopoietic stem cells.

Reduced expression of the transcription factor PU.1 is frequently associated with development of acute myeloid leukemia (AML), whereas elevated levels of CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) enhance maintenance of both normal and leukemic hematopoietic stem and progenitor cells (HSPCs). Recent findings indicate that PU.

CITED2 affects leukemic cell survival by interfering with p53 activation.

CITED2 (CBP/p300-interacting-transactivator-with-an-ED-rich-tail 2) is a regulator of the acetyltransferase CBP/p300 and elevated CITED2 levels are shown in a number of acute myeloid leukemia (AML). To study the in vivo role of CITED2 in AML maintenance, AML cells were transduced with a lentiviral construct for RNAi-mediated knockdown of CITED2. Mice transplanted with CITED2-knockdown AML cells (n=4) had a significantly longer survival compared to mice transplanted with control AML cells (P<0.

Essential Nonredundant Function of the Catalytic Activity of Histone Deacetylase 2 in Mouse Development.

The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes.

Divergent roles of HDAC1 and HDAC2 in the regulation of epidermal development and tumorigenesis.

The histone deacetylases HDAC1 and HDAC2 remove acetyl moieties from lysine residues of histones and other proteins and are important regulators of gene expression. By deleting different combinations of Hdac1 and Hdac2 alleles in the epidermis, we reveal a dosage-dependent effect of HDAC1/HDAC2 activity on epidermal proliferation and differentiation. Conditional ablation of either HDAC1 or HDAC2 in the epidermis leads to no obvious phenotype due to compensation by the upregulated paralogue.