General Updates | The underlying principles of CHIP and their relevance to myeloid neoplasms

CHIP stands for Clonal Hematopoiesis of Indeterminate Potential, and it’s the precursor for the myelodysplastic neoplasms and acute myeloid leukemia. It’s an early version of more active hematologic malignancies, and it’s defined as the expansion of the hematopoietic stem and progenitor cell pool by a somatic mutation in the absence of evidence of overt myeloid neoplasm. It’s an example of somatic mosaicism, but not germline mosaicism, and it’s not a germline mutation. It’s tissue-specific, and it’s, of course, restricted to the hematologic compartment. Now, the initial large-scale studies for CHIP were first reported in 2014, and multiple different groups have characterized CHIP back at that time. First, in Nature Medicine, Dr. Li Ding’s group from WashU analyzed blood-derived next-generation sequencing data from about 2,700 people from the Cancer Genome Atlas, and they found about 77 blood-specific mutations that were associated with advanced aging. They showed that about 5% to 6% of people above the age of 70 had subclinical hematopoietic expansion. Around the same time, just two months later, on Christmas Day in 2014, two large-scale studies were published back-to-back in the New England Journal of Medicine. One was by Steve McCarroll’s group from Harvard Department of Genetics. One was by Ben Ebert’s group from the Dana-Farber and from the Brigham and Women’s Hospital. 

Steve McCarroll’s group analyzed DNA from whole exome sequencing of peripheral blood from about 12,000 people from Swedish national patient registries. And they found clonal expansions in 10% of people above the age of 65, but only in 1% of people under the age of 50. And detectable clonal expansions were detected in genes such as DNMT3A, TET2, and ASXL1. And right around the same time, Ben Ebert’s group analyzed whole exome sequencing data from peripheral blood of more than 17,000 patients from 22 different population-based registries, including the Jackson Heart Study, as well as the Genetics of Type 2 Diabetes, or the GOT2D study. And they found that somatic mutations were found in 10% of healthy people above the age of 70, and again, these mutations were mostly found in epigenetic regulators. 

The pathogenesis of CHIP has been described at various groups such as the Sanger Institute as well as the Cambridge Stem Cell Institute. And the lifelong natural history is such that mutations typically begin in midlife, usually around the age range of about 40 or 50, and sometimes exogenous factors like chemotherapy or radiotherapy or cigarette smoking can negatively contribute to hematopoietic health. Inflammation can also contribute to propagation of pre-leukemic clones, and these pre-leukemic clones are usually enriched in mutations such as DNMT3A, TET2, and ASXL1. Damage to hematopoietic stem cells can result in selective expansion of pre-existing TP53 mutant or PPM1D mutant clones. And eventually, these cells become dysplastic. They can acquire mutations within RNA splicing genes such as SRSF2, SF3B1, U2AF1, and ZRSR2. And over time, with the success of accumulation of mutations, there can be mutations in the cohesin complex such as STAG2, SMC1A, SMC3, or RAD21. And finally, these cells can acquire proliferative ability because they gain mutations within proliferative signaling pathways. That includes mutations such as FLT3, JAK1, JAK2, JAK3, NRAS, KRAS, ABL1, CSF3R, KIT, and PTPN11. And thereafter, the myeloid compartment can become hyperproliferative, eventually resulting in a full-blown leukemia. So it’s really fascinating how the principles of CHIP can reflect the pathobiology of acute myeloid leukemia. And I think we have a lot to learn about leukemia by gaining a deeper understanding of subclinical clonal expansion.

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