Tag: leukaemia

Categories : CancerTags :

Protein Markers Distinguish Between Stable and Progressive Leukaemia

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Photo by Louis Reed on Unsplash

Scientists have identified protein markers which are related to the most common form of leukaemia.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the Western world. A new study published in the Journal of Leukocyte Biology shows that certain protein markers may indicate which patients have stable forms of CLL and which have more aggressive types.

Identifying these proteins may not only help determine patients’ prognoses but also point to potential therapeutic targets for investigators who are searching for new CLL treatments.

The study examined CLL B-cells’ proteomic profile from untreated CLL patients to see which biologic processes  that are affected early on and during disease evolution as stable or progressive. Of the 11 patients included in the study, six evolved to either progressive and five to stable disease. Purified B cells from the  patients were tested at two time points by liquid chromatography–tandem mass spectrometry. 

First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed protein, samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway.

An RNA-Seq study was conducted which showed 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. 

The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organisation, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. 

The study suggests that proteomic profiles of early stage CLL can discriminate progressive from stable disease. Furthermore, it appears RNA splicing dysregulation underlies CLL evolution, opening new avenues for biomarkers and therapy.

“The results offer a meaningful biological approach into the protein composition of CLL cells at an early stage of the disease, when the clinical characteristics of patients are similar and the course of the disease is difficult to predict. Our results showed that the protein profile can however predict how the disease will further evolve,” said lead author Cristina Bagacean, PhD, of CHU de Brest, in France. “This approach could identify putative therapeutic targets in order to prevent CLL progression.”

Source: Wiley

Journal information: Bagacean, C., et al. (2021) Identification of altered cell signaling pathways using proteomic profiling in stable and progressive chronic lymphocytic leukemia. Journal of Leukocyte Biology. doi.org/10.1002/JLB.4HI0620-392R.

Categories : CancerTags :

Avocado Compound May Be Useful in Leukaemia Therapy

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Avocados may be good for more than just an expensive toast topping. According to a new study from the University of Guelph a compound in avocados offers a potential route to improved leukaemia therapy.

The compound in questions targets an enzyme that scientists have identified for the first time as being critical to cancer cell growth, explained Dr Paul Spagnuolo, at the Department of Food Science.

The study focus was on acute myeloid leukaemia (AML), which is the most severe form of leukaemia. Most cases occur in people over age 65, with fewer than 10% of patients surviving five years after diagnosis.

Leukaemia cells have elevated levels of an enzyme called VLCAD involved in their metabolism, said Dr Spagnuolo.

“The cell relies on that pathway to survive,” he said, explaining that the compound is a likely candidate for drug therapy. “This is the first time VLCAD has been identified as a target in any cancer.”

Dr Spagnuolo’s team screened nutraceutical compounds among a variety of compounds, searching for any substance that could inhibit the enzyme. “Lo and behold, the best one was derived from avocado,” said Dr Spagnuolo.

Avocados have already been shown to improve lipid profiles, as well as helping to control weight, likely through increased satiation. His lab previously examined avocatin B, a fat molecule found only in avocados, for potential application in diabetes prevention and obesity management. He’s now keen to see it put to use in leukaemia patients.

“VLCAD can be a good marker to identify patients suitable for this type of therapy. It can also be a marker to measure the activity of the drug,” said Dr Spagnuolo. “That sets the stage for eventual use of this molecule in human clinical trials.”

Around half of patients over 65 diagnosed with AML currently enter palliative care. Some may undergo chemotherapy, but these treatments are often toxic and result in patients dying.

“There’s been a drive to find less toxic drugs that can be used,” he noted.

Referring to earlier work using avocatin B for diabetes, Spagnuolo said, “We completed a human study with this as an oral supplement and have been able to show that appreciable amounts are fairly well tolerated.”
The results of the study were published in the journal Blood.    

Source: Medical Xpress

Journal information: Matthew Tcheng et al, Very long chain fatty acid metabolism is required in acute myeloid leukemia, Blood (2021). DOI: 10.1182/blood.2020008551

Categories : Cancer PaediatricsTags :

Blood Mutation Explains High Leukaemia Rates in Children with Down’s

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According to a new study by researchers at the Linda Crnic Institute for Down Syndrome, the reason that children with Down syndrome have a drastically elevated risk of leukaemia is due to a more prevalent condition increasing blood stem cell mutation.

Children with Down syndrome are 20-times more likely to develop acute lymphocytic leukaemia (ALL) and 150-times more likely to develop acute myeloid leukaemia (AML) compared to their typical peers. The researchers found that the reason for this is that they are more likely to present with clonal haematopoiesis (CH), a process in which a blood stem cell acquires a genetic mutation that promotes replication.  

The findings add to a growing body of evidence linking immune dysregulation to a very different disease spectrum, whereby people with Down syndrome are highly predisposed to certain diseases such as leukaemia and autoimmune disorders, while being highly protected from others, such as solid tumours.

“We found a higher-than expected rate of CH in individuals with Down syndrome between the age of one to 20 years old,” said study author Dr Alexander Liggett, who as a doctoral candidate led the study in the lab of Dr James DeGregori, Professor of Biochemistry and Molecular Genetics. “It is a surprising finding, as the phenomenon is typically only observed in elderly people.”

The researchers used an advanced sequencing technique that they had developed, called FERMI, to blood samples from the Crnic Institute Human Trisome Project Biobank. Mutations were more likely to be detected in Down’s syndrome and also more likely to be oncogenic. In elderly people, oncogenic mutations are commonly found in the genes DNMT3A, TET2, ASXL1, TP53, and JAK2. In people with Down’s syndrome, oncogenic CH was found to be dominated by mutations of the TET2 gene.

“Given the increased risk of leukaemia that accompanies clonal expansion of blood cells carrying oncogenic mutations, these expansions may become an important biomarker of cancer risk in the future,” said Dr Liggett.

The study also found that CH in Down syndrome is associated with immune dysregulation biosignatures linked to diseases co-occurring with Down’s syndrome, including thyroiditis, Alzheimer’s disease, and leukaemia. This discovery opens new avenues in understanding the way CH impacts an array of health outcomes in Down syndrome and how to potentially counteract its effects.

“This is truly transformative. This team has identified a new trait of Down syndrome that has strong implications for understanding the appearance of comorbidities more common in this population, such as leukaemia and premature ageing,” said Dr. Joaquin Espinosa, Executive Director of the Crnic Institute. “The next step is to define the long-term impacts of this precocious clonal hematopoiesis and how to prevent its harmful effects.”

Source: News-Medical.Net

Journal information: Liggett, L.A., et al. (2021) Precocious clonal hematopoiesis in Down syndrome is accompanied by immune dysregulation. Gut. doi.org/10.1182/bloodadvances.2020003858.