p15Ink4b is Key in Dendritic Cell Development
Human dendritic cell
An important step in the initiation of leukemia is the ability of pre-leukemic and leukemic cells to evade the immune system. Dendritic cells are instrumental in maintaining the body’s immunity, and CCR scientists have shown for the first time that the tumor suppressor protein p15Ink4b regulates the differentiation and maturation of conventional dendritic cells.
Led by Juraj Bies, Ph.D., researchers in the Laboratory of Cellular Oncology used a mouse model previously developed in their lab to study the function of p15Ink4b in dendritic cells. Since previous studies showed that p15Ink4b had a role in the development of myeloid diseases, Bies and colleagues hypothesized that the loss of this protein affects the differentiation and maturation of dendritic cells, and therefore, it would affect the body’s immune responses and the development of acute myeloid leukemia (AML).
Dendritic cells seek out disease-causing substances and use antigens from these substances to stimulate the proliferation of T cells, which clear the body of pathogens and cancerous cells. Dendritic cells originate from hematopoietic stem cells, which are made in the bone marrow and develop special functions as they differentiate and mature.
The researchers found that mice with a p15Ink4b deficiency had significantly reduced numbers of dendritic cell precursors and conventional dendritic cells, and that these dendritic cells have significantly reduced ability to stimulate proper T cells response to pathogens and leukemic cells. Similarly, ex vivo experiments using cells derived from the mouse model showed substantially lower levels of expression of three proteins (MHCII, CD80, and CD86) that work together to activate T cells. To confirm that the loss of p15Ink4b specifically caused a developmental impairment of dendritic cells, the researchers re-introduced p15Ink4b and investigated its effects. The re-establishment of p15Ink4b restored expression of MHCII, CD80, and CD86, confirming a critical role for p15Ink4b in the development of dendritic cells.
Deficiency in p15Ink4b is frequently the result of methylation of the p15Ink4b gene, also known as the CDKN2B gene, which encodes the p15Ink4b protein. Methylation is the addition of a methyl group (a hydrocarbon radical) to a DNA molecule, and it causes the silencing, or inactivation, of a gene required for normal cell growth and development.
Methylation of p15Ink4b has been reported in more than 80 percent of AML patients. The researchers believe that their findings show that re-expression of this gene using methylation-inhibiting drugs may lead to a significant improvement of dendritic cell-based immunotherapy for patients with AML.
Summary Posted: 5/2012
Fares J, Koller R, Humeniuk R, Wolff L, Bies J. The tumor suppressor p15Ink4b regulates differentiation and maturation of conventional dendritic cells. Blood. 2012 Mar 28. PubMed Link
Reviewed by Vicky Perez
Note: All questions should be directed to TellCCR
- Repair Mechanism of UV-damaged DNA in Xeroderma Pigmentosum
- HIV envelope glycoprotein imaged at high resolution
- Combination Therapy Improves Survival in Prostate Cancer Model
- Metastasis Suppressor Gene Inactivates Actin-Based Mechanism of Tumor Cell Motility
- Identifying Regulators of the Immune Response to Dying Cells
- Examining Merkel Cell polyomavirus minor capsid proteins
- Using Proteomics to Identify Viral microRNA-Regulated Genes
- Blocking Glycolytic Metabolism Increases Memory T Cells and Antitumor Function
- Out-FOXing Pancreatic Cancer
- Visually Tracking Translocations in Living Cells
- Uncovering the Origin of Skin Side Effects from EGFR-Targeted Therapies
- Suboptimal Doses of Raltegravir Cause Aberrant HIV Integrations
- ROS is Required for Alternatively Activated Macrophage Differentiation
- Identifying a Mechanism for Crosstalk Between the Estrogen and Glucocorticoid Receptors