Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies

Aging is associated with multiple molecular and functional changes in haematopoietic cells. Most notably, the self-renewal and differentiation potential of hematopoietic stem cells (HSCs) are compromised, resulting in myeloid skewing, reduced output of red blood cells and decreased generation of immune cells. These changes result in anaemia, increased susceptibility for infections and higher prevalence of haematopoietic malignancies. In HSCs, age-associated global epigenetic changes have been identified. These epigenetic alterations in aged HSCs can occur randomly (epigenetic drift) or are the result of somatic mutations in genes encoding for epigenetic proteins. Mutations in loci that encode epigenetic modifiers occur frequently in patients with haematological malignancies, but also in healthy elderly individuals at risk to develop these. It may be possible to pharmacologically intervene in the aberrant epigenetic program of derailed HSCs to enforce normal haematopoiesis or treat age-related haematopoietic diseases. Over the past decade our molecular understanding of epigenetic regulation has rapidly increased and drugs targeting epigenetic modifications are increasingly part of treatment protocols. The reversibility of epigenetic modifications renders these targets for novel therapeutics. In this review we provide an overview of epigenetic changes that occur in aging HSCs and age-related malignancies and discuss related epigenetic drugs

3-Deazaadenosine alleviates senescence to promote cellular fitness and cell therapy efficiency in mice

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CBX7 Induces Self-Renewal of Human Normal and Malignant Hematopoietic Stem and Progenitor Cells by Canonical and Non-canonical Interactions

In this study, we demonstrate that, among all five CBX Polycomb proteins, only CBX7 possesses the ability to control self-renewal of human hematopoietic stem and progenitor cells (HSPCs). Xenotransplantation of CBX7-overexpressing HSPCs resulted in increased multi-lineage long-term engraftment and myelopoiesis. Gene expression and chromatin analyses revealed perturbations in genes involved in differentiation, DNA and chromatin maintenance, and cell cycle control. CBX7 is upregulated in acute myeloid leukemia (AML), and its genetic or pharmacological repression in AML cells inhibited proliferation and induced differentiation. Mass spectrometry analysis revealed several non-histone protein interactions between CBX7 and the H3K9 methyltransferases SETDB1, EHMT1, and EHMT2. These CBX7- binding proteins possess a trimethylated lysine peptide motif highly similar to the canonical CBX7 target H3K27me3. Depletion of SETDB1 in AML cells phenocopied repression of CBX7. We identify CBX7 as an important regulator of self-renewal and uncover non-canonical crosstalk between distinct pathways, revealing therapeutic opportunities for leukemia

Epigenetic Changes as a Target in Aging Haematopoietic Stem Cells and Age-Related Malignancies

Aging is associated with multiple molecular and functional changes in haematopoietic cells. Most notably, the self-renewal and differentiation potential of hematopoietic stem cells (HSCs) are compromised, resulting in myeloid skewing, reduced output of red blood cells and decreased generation of immune cells. These changes result in anaemia, increased susceptibility for infections and higher prevalence of haematopoietic malignancies. In HSCs, age-associated global epigenetic changes have been identified. These epigenetic alterations in aged HSCs can occur randomly (epigenetic drift) or are the result of somatic mutations in genes encoding for epigenetic proteins. Mutations in loci that encode epigenetic modifiers occur frequently in patients with haematological malignancies, but also in healthy elderly individuals at risk to develop these. It may be possible to pharmacologically intervene in the aberrant epigenetic program of derailed HSCs to enforce normal haematopoiesis or treat age-related haematopoietic diseases. Over the past decade our molecular understanding of epigenetic regulation has rapidly increased and drugs targeting epigenetic modifications are increasingly part of treatment protocols. The reversibility of epigenetic modifications renders these targets for novel therapeutics. In this review we provide an overview of epigenetic changes that occur in aging HSCs and age-related malignancies and discuss related epigenetic drugs

Comparative Study of Batch and Fluidized Bed Bioreactors for Lipase-Catalyzed Ethyl Cinnamate Synthesis

Ethyl cinnamate, an ester known as flavor and fragrance compound, has been synthesized using two immobilized bioreactor systems, batch and fluidized bed bioreactors. The enzyme used for this synthesis is a commercial lipase B preparation, Novozyme 435. Initial kinetic studies were conducted in both employed bioreactor configurations, and kinetic constants were obtained. Several models were tried for fitting of experimental data, but the best fit, for both bioreactors, was obtained when the ping-pong bi-bi mechanism was used. Interestingly enough, ethanol inhibition occurred in batch bioreactor, but it did not exist in the fluidized bed bioreactor. Solid-liquid mass transfer coefficients were calculated for both bioreactors to determine whether mass transfer limitations existed in either of these systems. The calculation of Damkohler numbers and Thiele modulus confirmed that mass transfer limitations had no effect on the overall reaction in both bioreactors