Novel Role of Histone Deacetylase 11 (HDAC11) in Hematopoiesis

Abstract 4728

HDAC11 is the newest member of the HDAC family. The physiological role of this HDAC was mainly unknown until the discovery by our group that HDAC11 regulates IL-10 gene expression in immune cells in-vitro¹. To better elucidate the role of HDAC11 in lineage differentiation and hematopoiesis, we have utilized an HDAC11 promoter-driven eGFP reporter transgenic mice (TgHDAC11-eGFP) which allow us to “visualize” dynamic changes in HDAC11 gene expression/transcriptional activity in immune cell compartments in vivo. Thus far, our data indicates that in hematopoietic stem cells (CD34⁺/Lin⁻), transcriptional activation of HDAC11, indicated by eGFP expression appears to be absent. Also, no eGFP expression is seen in the common lymphoid progenitors (CLP-CD34⁺/CD127⁺/CD117^low/Lin⁻) and/or the common myeloid progenitors (CMP-CD34⁺/CD127⁻/CD117^high/Lin⁻). In the T-cell compartment, transcriptional activation of HDAC11 increases from CD4⁻/CD8⁻ T-cells to CD4⁺/CD8⁺ T-cells to single positive CD4⁺ and CD8⁺ T-cells. The expression of eGFP then decreases from naive to effector memory, but then increases again at terminal effector memory. Expression of eGFP, in the bone marrow moderately increase transitioning from Pro-B-cells (CD3⁻/CD200⁺/CD19^low/CD43^high), Pre-B-cells (CD3⁻/CD200⁺/CD19^int/CD43^int), and Immature (CD3^−/CD200⁺/CD19^high/CD43^low) respectively. Interestingly eGFP expression doubles in the B-1 (CD3⁻/CD19⁺/CD200^low/−) stage of differentiation in the periphery. Remarkably, eGFP expression appears to be at its highest in the plasma cell compartment of the bone marrow. A second murine model also available to us, HDAC11 knockout mice (HDAC11KO) were also utilize to confirm these findings. When compared to wild-type mice, HDAC11KO mice have increased B-1 B-cells and decreased plasma cells. In the myeloid compartment, using TgHDAC11-eGFP mice, expression of HDAC11 transcript in myeloblasts (CD34⁺/CD45^dim/CD117^+/Lin-) appears to be absent. However the expression increases to 50% in the promyelocytes (Side Scatter high/CD45^dim/+/CD34⁻/CD117⁺) and to 98% in the granulocytes specifically Neutrophils (Side scatter high/CD45dim+/CD34⁻/CD117⁻/CD14⁻/Ly6G^bright+). Strikingly, monocytes (dendritic cells and macrophages) showed no expression of eGFP.

Taken together, HDAC11 appears to be essential for proper B-cells and T-cell differentiation. It also seems to play a critical role in differentiation of granulocytes and monocytes. Therefore it is plausible that HDAC11 might function as a regulator of hematopoietic differentiation and expansion in vivo. A better understanding of this previously unknown role of HDAC11 in hematopoiesis might lead to targeted epigenetic therapies in hematological malignancies to influence the appropriate differentiation of these cells, and possibly augmenting the efficacy of immunotherapeutic approaches against malignancies.