Project description:Determine the effects of HDAC1/2-selective chemical inhibtion on the gene expression profiles of erythroid progenitors derived from human CD34+ bone marrow cells.
Project description:Establish the DNA binding profiles of HDAC1, HDAC2 and Gata2 in erythroid progenitors derived from human CD34+ bone marrow cells. Determine the effects of HDAC1/2 inhibition on the DNA binding profiles of Gata2.
Project description:RNA-sequencing of megakaryocyte-erythroid progenitors of CALRdel52/+ MxCre mice treated with either vehicle or 2-deoxy-D-glucose for 21 days.
Project description:Gene expression data from BE(2)-C cells treated in triplicate with either vehicle (DMSO), 5 M-NM-<M all-trans retinoic acid (ATRA), 1 mM valproic acid (VPA), or 5 M-NM-<M ATRA + 1 mM VPA for 6, 24, or 72 hours. Genome-wide expression profiling was performed using Affymetrix U133A microarrays. While cytotoxic chemotherapy remains the hallmark of cancer treatment, intensive regimens fall short in many malignancies, including high-risk neuroblastoma. One alternative strategy is to therapeutically promote tumor differentiation. We created a gene expression signature to measure neuroblast maturation, adapted it to a high-throughput platform, and screened a diversity oriented synthesis-generated small-molecule library for differentiation inducers. We identified BRD8430, containing a nine-membered lactam, an ortho-amino anilide functionality, and three chiral centers, as a selective Class I histone deacetylase (HDAC) inhibitor (HDAC1 > 2 > 3). Further investigation demonstrated that selective HDAC1/HDAC2 inhibition using compounds or RNA interference induced differentiation and decreased viability in neuroblastoma cell lines. Combined treatment with 13-cis retinoic acid augmented these effects and enhanced activation of retinoic acid signaling. Therefore, by applying a chemical genomic screening approach we identified selective HDAC1/HDAC2 inhibition as a strategy to induce neuroblastoma differentiation. BE(2)-C cells were treated in triplicate with either vehicle (DMSO), 5 M-NM-<M all-trans retinoic acid (ATRA), 1 mM valproic acid (VPA), or 5 M-NM-<M ATRA + 1 mM VPA for 6, 24, or 72 hours. Genome-wide expression profiling was performed using Affymetrix U133A microarrays [HT-HG_U133A Early Access].
Project description:Determine the differences in gene expression profiles of MV-4-11 AML cells treated with HDAC1/2-selective inhibition, azacitidine, or the combination of the two agents. Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic stem cell disorders characterized by defects in myeloid differentiation and increased proliferation of neoplastic hematopoietic precursor cells. Outcomes for patients with AML remain poor, highlighting the need for novel treatment options. Aberrant epigenetic regulation plays an important role in the pathogenesis of AML, and inhibitors of DNA methyltransferase or histone deacetylase (HDAC) enzymes have exhibited activity in preclinical AML models. Combination studies with HDAC inhibitors plus DNA methyltransferase inhibitors have suggested beneficial clinical activity in AML, however the toxicity profiles of non-selective HDAC inhibitors in the combination setting limit their clinical utility. In this work, we describe the preclinical development of selective inhibitors of HDAC1 and HDAC2, which are hypothesized to have improved safety profiles, for combination therapy in AML. We demonstrate that selective inhibition of HDAC1 and HDAC2 is sufficient to achieve efficacy both as a single agent and in combination with azacitidine in preclinical models of AML, including established AML cell lines, leukemia cells from AML patient bone marrow samples and in vivo xenograft models of human AML. Gene expression profiling of AML cells treated with either an HDAC1/2 inhibitor, azacitidine, or the combination of both have identified a list of genes involved in transcription and cell cycle regulation as potential mediators of the combinatorial effects of HDAC1/2 inhibition with azacitidine. Together, these findings support the clinical evaluation of selective HDAC1/2 inhibitors in combination with azacitidine in AML patients.
