May 30, 2017

A research team from the National University of Singapore (NUS) led by Assistant Professor Takaomi Sanda, Principal Investigator from the Cancer Science Institute of Singapore and Department of Medicine at NUS Yong Loo Lin School of Medicine, has provided new insights into the molecular mechanism affecting how genes are produced during normal T-cell development, and contributing to leukaemia formation. Results of the study have been published in the journal Leukemia.

T-cells are a type of white blood cell which develops in the thymus (hence the name T-cell), a primary lymphoid organ. These cells play an indispensable role in the body's cellular defence system. In T-cell acute lymphoblastic leukaemia (T-ALL), which is a cancer of the white blood cells, T-cells carry genetic mutations which cause them to multiply uncontrollably. Production of genes during T-cell development is strictly controlled by the body. Different genes are turned 'on' and 'off' at various stages of T-cell development, in order to ensure T-cells become fully functional in the immune system.

TAL1 triggers the super-enhancer 'switch'

Specifically, the research team studied the protein TAL1, which is encoded by a cancer causing gene previously found to contribute to the development of T-ALL, and discovered that TAL1 activates a 'molecular switch' called a super-enhancer, which subsequently leads to a cluster of genes called GIMAP being activated. This may result in T-cell precursors growing abnormally and not developing into functional T-cells in the body, leading to the development of T-ALL.

Super-enhancers are regions of DNA that increase production of genes linked to important cellular decisions. They can be sensitive to disturbances and occur frequently at cancer genes. The activation of the super-enhancer induces genes to be abnormally activated, instead of being strictly controlled.

Asst Prof Sanda said, "Currently, most of the patients with T-ALL are young children. While recent improvements in chemotherapy have significantly boosted cure rates for T-ALL, the introduction of intensive chemotherapy causes both short- and long-term adverse effects. Moreover, there are only a limited number of new drugs with specific activity against malignant T-cells. Moving forward, we are looking into identifying potential therapeutic compounds that inhibits the activation of this super-enhancer. We hope to be able to translate it into meaningful therapies for patients afflicted by T-ALL."

Explore further: Preventing too much immunity

More information: W S Liau et al. Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia, Leukemia (2016). DOI: 10.1038/leu.2016.392

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New insights into T-cell acute lymphoblastic leukaemia development - Medical Xpress

May 29, 2017

Diabetic patients frequently have lesions on their feet that are very difficult to heal due to poor blood circulation. In cases of serious non-healing infections, a decision to amputate could be made. A new therapeutic approach, presented recently in the Journal of Investigative Dermatology by Canadian researchers affiliated with the University of Montreal Hospital Research Centre (CRCHUM), could prevent these complications by promoting wound healing.

The solution isn't what you might expect, not just another antibiotic ointment or other prescription medication. It's the approach that's different, a way to heal through personalized medicine. "We discovered a way to modify specific white blood cells - the macrophages - and make them capable of accelerating cutaneous healing," explained nephrologist Jean-Franois Cailhier, a CRCHUM researcher and professor at the University of Montreal.

It has long been known that macrophages play a key role in the normal wound healing process. These white cells specialize in major cellular clean-up processes and are essential for tissue repair; they accelerate healing while maintaining a balance between inflammatory and anti-inflammatory reactions (pro-reparation).

"When a wound doesn't heal, it might be secondary to enhanced inflammation and not enough anti-inflammatory activity," explained Cailhier. "We discovered that macrophage behaviour can be controlled so as to tip the balance toward cell repair by means of a special protein called Milk Fat Globule Epidermal Growth Factor-8, or MFG-E8."

Cailhier's team first showed that when there is a skin lesion, MFG-E8 calls for an anti-inflammatory and pro-reparatory reaction in the macrophages. Without this protein, the lesions heal much more slowly. Then the researchers developed a treatment by adoptive cell transfer in order to amplify the healing process.

Adoptive cell transfer consists in treating the patient using his or her own cells, which are harvested, treated, then re-injected in order to exert their action on an organ. This immunotherapeutic strategy is usually used to treat various types of cancer. This is the first time it has been shown to also be useful in reprogramming cells to facilitate healing of the skin.

"We used stem cells derived from murine bone marrow to obtain macrophages, which we treated ex vivo with the MFG-E8 protein before re-injecting them into the mice, and we quickly noticed an acceleration of healing," said Dr. Patrick Laplante, Cailhier's research assistant and first author of the study.

Added Dr. Cailhier, "the MFG-E8 protein, by acting directly upon macrophages, can generate cells that will orchestrate accelerated cutaneous healing."

The beauty of this therapy is that the patient (in this case the mouse) is not exposed to the protein itself. Indeed, as Dr. Cailhier explained, "if we were to inject the MFG-E8 protein directly into the body there could be effects, distant from the wound, upon all the cells that are sensitive to MFG-E8, which could lead to excess repair of the skin causing aberrant scars named keloids. The major advantage [of this treatment] is that we only administer reprogrammed cells, and we find that they are capable of creating the environment needed to accelerate scar formation. We have indeed discovered the unbelievable potential of the macrophage to make healing possible by simple ex vivo treatment."

What now remains to be done is to test this personalized treatment using human cells. Thereafter, the goal will be to develop a program of human cell therapy for diabetic patients and for victims of severe burns. It will take several years of research before this stage can be reached.

This advanced personalized treatment could also make all the difference in treating cases of challenging wounds. According to the World Health Organization, diabetes affects 8.5% of the global population, and amputation rates of the lower extremities are 10 to 20 times higher in diabetics. "If, with this treatment, we can succeed in closing wounds and promoting healing of diabetic ulcers, we might be able to avoid amputations," Dr. Cailhier said.

"Serious burn victims could also benefit," he added. "By accelerating and streamlining the healing of burns, we may be able to reduce the infections and keloids that unfortunately develop much too often in such patients." Cancer patients requiring extensive reconstruction surgery could also benefit, he said.

Explore further: Macrophages need two signals to begin healing process

More information: Patrick Laplante et al, MFG-E8 Reprogramming of Macrophages Promotes Wound Healing by Increased bFGF Production and Fibroblast Functions, Journal of Investigative Dermatology (2017). DOI: 10.1016/j.jid.2017.04.030

Journal reference: Journal of Investigative Dermatology

Provided by: University of Montreal Hospital Research Centre (CRCHUM)

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Healing wounds with cell therapy - Medical Xpress

HERSHEY, Pa. Scientists could be one step closer to developing vaccines against viruses such as Zika, West Nile or HIV, according to Penn State College of Medicine researchers.

Most current vaccines work by stimulating a class of white blood cells called B cells to make antibodies that circulate and control infections in the blood. For decades, scientists have been seeking a new type of vaccine that activates another player in the immune system called a T cell to fight off infections within different organs.

A small number of a type of T cell, called memory T cells, are generated following an infection or immunization. Some memory T cells patrol the body looking for repeat infection, while others migrate into organs and remain there; these are called tissue-resident memory cells. These cells can be found where viruses and bacteria can get into the body, such as the skin, the gut and the female reproductive tract, as well as organs that are highly prone to injury, such as the brain.

In a study a team of researchers, led by Aron E. Lukacher, chair and professor of microbiology and immunology, and Saumya Maru, a medical and doctoral student, has uncovered more details about what it takes to generate a good tissue-resident memory T-cell response against repeat infections. They report their results in PLOS Pathogens.

Working with mouse polyomavirus, the researchers developed a library of genetically altered viruses that stimulated T cell receptors at different strength levels in mice. Virus variants with weaker stimulation gave rise to tissue-resident memory T cells in the mouse brain that were better able to fight off a second infection there.

Adjusting the strength of T cell receptor stimulation in effect making it weaker promoted the generation of these resident memory T cells in the brain, Lukacher said. The weaker the stimulation, the better the memory.

Now that importance of tissue-resident memory T cells in thwarting infections in organs has been identified, vaccine researchers have become interested in learning about factors that promote the number and function of thesecells.

If successful, people in the future who are inoculated with vaccines that induce a strong tissue-resident memory T cell response will be protected from the infection much more efficiently, Lukacher said. Very certainly having more and better functioning memory T cells will clear out the infection much more rapidly.

Other researchers on this project were Todd D. Schell, professor of microbiology and immunology, and Ge Jin, research technologist, both at Penn State College of Medicine.

The National Institute of Allergy and Infectious Diseases, the National Institute of Neurological Disorders and Stroke, and the National Institute of Neurological Disorders and Stroke grant funded this research.

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Understanding T cell activation could lead to new vaccines - Penn State News