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Clonal hematopoiesis of indeterminate potential (CHIP) is a state in which somatic mutations are found in the cells of the blood or bone marrow but does not meet the World Health Organization (WHO) criteria for hematologic malignancies. Myeloproliferative neoplasms (MPN) are rare clonal neoplastic disorders of the myeloid hematopoietic stem cells (HSCs) with recurrent somatic mutations that typically activate growth factor signaling pathways. The heterogeneity observed in patients presenting with MPN has highlighted the importance of having a comprehensive knowledge of the molecular pathogenesis of MPN.
During the Texas Virtual MPN Workshop (TMW) 2021: Second Annual Workshop and Meeting, Dr Rafael Bejar presented a session on CHIP and its implications for MPN.1 The session provided an overview of the molecular pathogenesis of MPN, risks of clonal hematopoiesis (CH), and implications of CHIP; including targeting CHIP for therapeutic benefit.
Bejar explained the typical characteristic features of MPN including their clonal capability with recurrent somatic mutations and hyperproliferation of one or more mature myeloid cell lines and expansion of the clonal HSC.
MPN are at an increased risk of transformation to acute myeloid leukemia (AML) and have driver mutations that activate growth factor signaling pathways (JAK2V617F, TRORW515 or CALRmut). MPN is disposed to continuous clonal evolution, leading to more advanced stages of disease such as myelodysplastic syndrome (MDS) or myelofibrosis or AML.
The WHO classification of MPN is diagnostic; however, there are other modifying mutations that are not unique to MPN such as those in splicing factors, epigenetic regulators, transcription factors, and genes like TP53 that have strong modulating effects on the genetic phenotype and clinical outcomes in patients with MPN. Bejar provided examples from Rumi, et al.2 elucidating the differential impact of driver mutations (CALR, JAK2, MPL and TN) on the manifestation of the disease and Tefferi, et al.3 demonstrating that different mutations within a single gene can have a dissimilar impact on the progression of the disease. For instance, CALR type-1 mutations may have better survival compared with CALR type-2 mutations. Bejar also presented studies that show the benefits of classifying MPN based on their genetic features as opposed to their clinical features.
Guijarro-Hernandez, et al.4 provides a broad overview of the signaling pathway involved in MPN, highlighting that somatic driver mutations could affect epigenetic regulation, tumor suppression, transcription regulation, splicing, and other signaling pathways, leading to the modification of some disease features and adding complexity to their molecular pathogenesis.
Grinfeld, et al’s.5 study on the genomic landscape of MPN, found that along with the common canonical mutations JAK2 and CALR, there were other epigenetic regulators TET2, ASXL1 and DNMT3A, mostly found in patients with CH, suggesting that mutations from non-canonical hot spots should also be considered in the prognosis of MPN. Genetic classification can be used to create new groupings, clustering patients with similar mutations and outcomes.
Bejar explains how both common and rare variations are important in understanding their predisposition to MPN. Haplotype 46/1 GGCC is the most common variation predisposing to JAK2 as well as non-JAK2 mutations, leading to MPN.
Pegliasco, et al.6 found that CH existed in most healthy carriers of the rare germline CNVdupATG2B/GSKIP (chromosome 14) and facilitated early recognition of disease onset. TET2 pathway also had a major role in the onset of the disease indicating that germline CNVdupATG2B/GSKIP may induce TET2-mutated CH independently.
Here, Bejar explains how CH applies to MPN and provides examples of studies investigating CH. The self-renewal and differentiation of HSCs is tightly controlled and when driver mutations cause an imbalance that favors HSC expansion, this leads to corrupted hematopoiesis. The disease path (e.g., MPN, MDS, or AML) is dependent upon the type and evolution of the mutations and not all mutations have a disease phenotype. Such cases are defined as CHIP.
The Cancer Genome Atlas (TCGA) identified a high frequency of somatic mutations in the blood of patients with solid tumors, specifically in genes associated with myeloid cancers like DNMT3A, TET2, ASXL1, TP53, JAK2 and the presence of these mutations was strongly correlated with age.7 Subsequent genome-wide studies investigated mutations in normal individuals and found that somatic mutations like DNMT3A, TET2, ASXL1, TP53, and JAK2 were found in nearly 15% of individuals aged 70–80 years with detectable clones in their blood. Although CH increases the relative risk of malignancy, the absolute risk remained very low at 0.5-1% per year on average. Patients with higher abundance of clonal mutations were more likely to progress to MDS or AML but there were many patients who did not develop any malignancies despite a high burden of clonal mutations.
Using more sensitive methodology, Young, et al.8 observed CH, frequently with DNMT3A and TET2 mutations, in 95% of the healthy participants in their study (n = 20; age range, 50–60 years) which were often still present more than 10 years later, suggesting a long-lived HSC origin. Although not necessarily giving rise to a clonal disease, these mutations may set the stage for clonal expansion upon selective pressures.
A study of saliva samples from patients with MPN, using the 23andMe test, demonstrated a high rate of JAK2V617F mutations. Interestingly, this test also showed many patients in the general population (0.2%) had high abundance of clones with acquired uniparental disomy and the incidence of JAK2V617F increased with age. The study also found that other germline variations (TERT, TET2, and SH2B3) were associated with JAK2V617F predisposing to MPN.9
A large-scale genome-wide association study meta-analysis10 of MPN (n = 3,797) identified several hematopoietic traits spanning different lineages and associated increased MPN risk with longer leukocyte telomere length and other clonal hematopoietic states, collectively implicating HSC function and self-renewal. The study also indicated the likely roles of CHEK2, ATM, MLKN1, MECOM, and GFI1B in changing HSC function to confer disease risk.
A Danish screening study11 found that participants with positive mutations showed higher blood cell counts, raising concerns of MPN underdiagnosis. The order of acquisition of mutations preceding MPN, i.e., JAK2V617F before TET2, and vice versa, may have an impact on the prognosis of the patient.
Overall, the evidence is suggestive of a germline predisposition to develop these clonal states and consequently MPN.
Validated in several studies, it has been shown that mortality is higher in patients with CH, not driven by hematologic malignancy but by cardiovascular disease (CVD). Risk of CVD was independent of the gene mutation defining CH, however, JAK2V617F CH had the highest risk. Mouse models of CH have shown increased risk of atherosclerosis and an increased inflammatory gene signature and moreover have indicated that JAK2 CHIP is associated with adverse cardiovascular function.
The CANTOS study12 investigated the efficacy of canakinumab, a monoclonal antibody targeting interleukin-1β and found that it reduced the cardiovascular risk in patients already at high risk for CVD but was associated with substantial toxicity so was not carried forward. However, a retrospective analysis showed that most of the benefit occurred in patients with CHIP (16% risk reduction) and particularly those in CHIP driven by TET2 mutations (64% risk reduction).
Potential therapeutic strategies to prevent progression of MPN and development of cardiovascular risk may include use of statins, metformin, NRLP3 inhibition, anti-IL6/18 and JAK inhibition or anti-coagulation in JAK2 mutant patients.
Overall, CHIP is widespread and is highly age dependent. Patterns of CHIP mutations may be informative to predict progression to MPN or other myeloid neoplasms. Additionally, MPN-associated CHIP mutations are of clinical significance as they increase cardiovascular disease risk and for JAK2 mutations can be prothrombotic.
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