Choline Kinase Alpha Inhibition is a Mutation Agnostic Therapeutic Vulnerability in Clonal Hematopoiesis

Why it matters

As people age, some blood-forming stem cells pick up mutations that give them a growth advantage, so their descendants slowly take over a share of the blood. This is called clonal hematopoiesis, and it is one of the clearest examples of somatic mutation shaping ageing. It is linked to higher risk of blood cancers, heart disease and death from any cause, but there are few treatment options. Because the mutations occur in different genes in different people, a treatment that works across mutations would be especially useful.

What they did

The team used colour barcoding of blood stem and progenitor cells together with mosaic mutagenesis in zebrafish, a way of making mutations in only some cells and tracking which clones expand. In cells carrying mutations in asxl1, one of the most common clonal hematopoiesis genes, they looked for altered metabolism. They then reduced the activity of choline kinase alpha, an enzyme in the pathway that makes phosphatidylcholine, a main building block of cell membranes, and checked whether the mutant clones still expanded. They repeated key tests in a mouse model with DNMT3A mutations and a human TET2 model, tested whether adding back platelet activating factor (PAF) reversed the effect, and used stem cells from the blood of patients with ASXL1 mutations in a lab clonal competition test.

What they found

ASXL1-mutant stem cells showed disturbed choline metabolism and increased phosphatidylcholine production through choline kinase alpha. Suppressing this choline flow reduced ASXL1-driven clonal expansion, and the same effect held in the DNMT3A mouse model and the human TET2 model. Mechanistically, the phosphatidylcholine made through this route supports the production of PAF, a lipid signalling molecule. Adding PAF from outside overcame the effect of blocking the enzyme in the ASXL1 and TET2 models. In blood stem cells from patients with ASXL1 mutations, interfering with PAF signalling lowered their competitive potential, and the same enzyme-to-PAF link was present in TET2-mutant cells. The authors conclude that this is a shared metabolic dependency across the three most common clonal hematopoiesis genotypes.

Limits

This is a preprint and has not been peer reviewed. The synopsis is based on the abstract only. The human evidence comes from cells grown outside the body, not from treated patients, so whether blocking the enzyme is safe or effective in people is unknown. The abstract does not report whether targeting this pathway affects healthy blood stem cells or the diseases linked to clonal hematopoiesis, and it gives no sample sizes or effect sizes.

Key terms

Clonal hematopoiesis (CH)

An age-related state in which blood stem cells carrying a somatic mutation outgrow their neighbours and make up a large share of blood cells.

Somatic mutation

A DNA change that arises in a body cell during life, rather than being inherited.

ASXL1, DNMT3A, TET2

The three genes most often mutated in clonal hematopoiesis; all help control how genes are switched on and off.

Choline kinase alpha (CHKA)

An enzyme that adds a phosphate to choline, the first step in making the membrane lipid phosphatidylcholine.

Phosphatidylcholine

A major fat-based building block of cell membranes, made from choline.

Platelet activating factor (PAF)

A lipid signalling molecule made from phosphatidylcholine that acts on cells through its own receptor.