Clonal hematopoiesis (CH) happens when a hematopoietic stem cell, which may differentiate into a variety of blood cells, starts producing cells with the same genetic mutation. The genetic pattern of these blood cells differs from that of the rest of your blood cells. Clonal hematopoiesis (CH) occurs when hematopoietic stem and progenitor cells (HSPCs) acquire somatic mutations in oncogenic driver genes, resulting in the development of blood cell clones in otherwise healthy people. CH is unusual in younger people, but its incidence rises dramatically and steadily beyond the age of 60, when it may be diagnosed at 10%-20%  frequency.

Clonal Hematopoiesis is a major risk factor for thromboembolism and cardiovascular disease, as well as a pre-malignant state for myeloid neoplasms such as acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS).

Clonal hematopoiesis in the older was originally discovered in research that found that about 25% of healthy women over the age of 65 exhibits a skewed pattern of X-chromosome inactivation in peripheral blood cells, which is sometimes linked to TET2 mutations.

Mutations Due To Clonal Hematopoiesis

Clonal Hematopoiesis In Old Population

It’s been proposed that when haematopoietic stem cells age, they acquire random somatic mutations, which might lead to clonal growth, secondary hits, and ultimately clinically visible illness. Somatic mutations in haematopoietic cells are found in approximately 90% of individuals with myelodysplastic syndrome. Furthermore, mutations in potential cancer drivers such DNMT3A, TET2, and ASXL1 influence over 90% of clonal haematopoiesis and are among the most often affected genes in myelodysplastic syndrome.

Somatic mutations in haematopoietic cells may be clinically significant or an unintentional discovery in older individuals with slightly abnormal haemograms who do not meet the basic diagnostic criteria for myelodysplastic syndrome.

Loss-of-function mutations in the epigenetic regulators DNMT3A and TET2 have been demonstrated to de-repress genes for inflammatory mediators such as interleukin-1 (IL-1) and interleukin-6 (IL-6) mechanistically. However, a later study has established that the presence of Clonal Hematopoiesis in peripheral blood cells is linked to a roughly doubling in the chance of developing cancer. Clonal Hematopoiesis has been linked to coronary heart disease in humans, indicating that it is related to inflammation and atherosclerosis.

DNA Methyltransferase 3A (DNMT3A), Ten-Eleven-Translocation 2 (TET2), and Additional Sex Combs-like are the most often altered genes in people with Clonal Hematopoiesis. Janus Kinase 2 (JAK2), Protein 1 (ASXL1), Tumor Protein p53 (TP53), Janus Kinase 1 (ASXL1), Janus Kinase 2 (JAK2), Janus Kinase 2 (JAK2), Phosphatase, Mg2+/Mn2+ Dependent 1D (PPM1D) and Splicing Factor 3b, are mutated often in myeloid neoplasms.

Clonal Hematopoiesis and Cancer

Clonal Hematopoiesis is characterised by a single somatic mutation and the absence of overt malignancy. Myeloid malignancies, such as acute myeloid leukaemia, myelodysplastic syndrome, myeloproliferative neoplasms, and certain lymphomas, share the mutations identified in persons with CHIP. In most situations, transition to malignancy necessitates the accumulation of several mutations in sequential order.

In the blood of around 2% of people over the age of 75, large-scale somatic events such as chromosomal insertions and deletions (indels) and loss of heterozygosity occur. In the bone marrow of individuals with acute myeloid leukaemia (AML) who are in remission, preleukemic hematopoietic stem cells with just the starting driver mutation have been discovered. The chance of getting acute myeloid leukaemia was projected to be three to five times greater in those with CHIP than in people who didn’t have it.

When compared to those without CHIP, people with CHIP have a tenfold increased chance of having haematological cancer, with the risk increasing with the size of the clone. Overall, the probability of malignancy transition is around 05%–1% each year, which is similar to the risk of transformation of monoclonal gammopathy of unknown significance multiple myeloma.

Clonal Hematopoiesis and Non Lethal Diseases

Clonal Hematopoiesis is linked to a higher overall mortality rate.   Considering blood cancers are relatively infrequent, a higher risk of haematological malignancies alone can not explain this mortality risk. Clonal Hematopoiesis has been linked to myocardial infarction in major genetic investigations, with a hazard ratio higher than several of the recognised risk factors for cardiovascular diseases, such as blood pressure, cholesterol. Clonal Hematopoiesis nearly doubles the risk of myocardial infarction, and studies show that it has a direct role in atherosclerosis development. 24,52 The modified inflammatory response in the blood cells of Clonal Hematopoiesis patients has been demonstrated to impact a wide spectrum of disease mechanisms, notably in inflammatory illnesses associated with ageing.

Due to these links, clinicians outside of the field of haematology may conduct further next-generation sequencing tests to see if Clonal Hematopoiesis is playing a role in the underlying pathophysiology. This might provide further difficulties, not only in terms of interpreting next-generation sequencing data but also in terms of following demands for the haematological examination of clinically relevant samples.

Conclusion

In the old population, clonal hematopoiesis was linked to poor survival. Various mutational patterns indicate different levels of risk for myeloid malignancies and inflammatory/vascular disorders. Non-mutational variables, such as early alterations in red blood cell indices, may help identify individuals who are at a higher risk of developing myeloid malignancies.

Thus it can be concluded that in the elderly, somatic mutations that induce clonal growth of blood cells were prevalent, with DNMT3A, TET2, and ASXL1 being the most common.

References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008978/

https://www.nature.com/articles/nm.3733

https://pubmed.ncbi.nlm.nih.gov/33010619/

https://pubmed.ncbi.nlm.nih.gov/29141946/