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
- Investigating Genetic Alterations in Bladder Cancer
- Histone Variant Regulates DNA Repair via Chromatin Condensation
- DNA Damage Repair Factors have a Tumor Promoting Role in MLL-fusion Leukemia
- COX-2 – A Novel Target for Reducing Tumor Angiogenesis and Metastasis
- Identifying Monoclonal Antibodies that Potently Inhibit MERS-CoV
- HIV Integration at Certain Sites in Host DNA is Linked to the Expansion and Persistence of Infected Cells
- Mitochondrial Enzyme Plays Critical Role in Chemotherapy-Induced Heart Damage
- Novel Structure of Ty3 Reverse Transcriptase
- Investigating the Role of NOS2 in Breast Cancer
- Large Population-Based Study Reveals Disparities in Myeloma Precursor Disease
- Small Molecule Disrupts Abnormal Gene Fusion Associated with Leukemia
- Changes in miRNAs Signal High-Risk HPV Infections
- Ionizing Radiation Enhances Monoclonal Antibody Effectiveness through Increased Target Expression
- Global Gene Expression Profiles Identify Metastasis Regulatory Networks