Journal articles: 'Clonal hematopoiesis of indeterminate potential'

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Papa, Veronica, Luisa Marracino, Francesca Fortini, Paola Rizzo, Gianluca Campo, Mauro Vaccarezza, and Francesco Vieceli Dalla Sega. "Translating Evidence from Clonal Hematopoiesis to Cardiovascular Disease: A Systematic Review." Journal of Clinical Medicine 9, no. 8 (August 2, 2020): 2480. http://dx.doi.org/10.3390/jcm9082480.

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Some random mutations can confer a selective advantage to a hematopoietic stem cell. As a result, mutated hematopoietic stem cells can give rise to a significant proportion of mutated clones of blood cells. This event is known as “clonal hematopoiesis.” Clonal hematopoiesis is closely associated with age, and carriers show an increased risk of developing blood cancers. Clonal hematopoiesis of indeterminate potential is defined by the presence of clones carrying a mutation associated with a blood neoplasm without obvious hematological malignancies. Unexpectedly, in recent years, it has emerged that clonal hematopoiesis of indeterminate potential carriers also have an increased risk of developing cardiovascular disease. Mechanisms linking clonal hematopoiesis of indeterminate potential to cardiovascular disease are only partially known. Findings in animal models indicate that clonal hematopoiesis of indeterminate potential-related mutations amplify inflammatory responses. Consistently, clinical studies have revealed that clonal hematopoiesis of indeterminate potential carriers display increased levels of inflammatory markers. In this review, we describe progress in our understanding of clonal hematopoiesis in the context of cancer, and we discuss the most recent findings linking clonal hematopoiesis of indeterminate potential and cardiovascular diseases.

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Steensma, David P. "Clinical consequences of clonal hematopoiesis of indeterminate potential." Blood Advances 2, no. 22 (November 27, 2018): 3404–10. http://dx.doi.org/10.1182/bloodadvances.2018020222.

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Abstract Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

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Steensma, David P. "Clinical consequences of clonal hematopoiesis of indeterminate potential." Hematology 2018, no. 1 (November 30, 2018): 264–69. http://dx.doi.org/10.1182/asheducation-2018.1.264.

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Abstract Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.

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Boettcher, Steffen, and Benjamin L. Ebert. "Clonal Hematopoiesis of Indeterminate Potential." Journal of Clinical Oncology 37, no. 5 (February 10, 2019): 419–22. http://dx.doi.org/10.1200/jco.2018.79.3588.

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Steensma, David P., Rafael Bejar, Siddhartha Jaiswal, R. Coleman Lindsley, Mikkael A. Sekeres, Robert P. Hasserjian, and Benjamin L. Ebert. "Clonal hematopoiesis of indeterminate potential and its distinction from myelodysplastic syndromes." Blood 126, no. 1 (July 2, 2015): 9–16. http://dx.doi.org/10.1182/blood-2015-03-631747.

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Abstract Recent genetic analyses of large populations have revealed that somatic mutations in hematopoietic cells leading to clonal expansion are commonly acquired during human aging. Clonally restricted hematopoiesis is associated with an increased risk of subsequent diagnosis of myeloid or lymphoid neoplasia and increased all-cause mortality. Although myelodysplastic syndromes (MDS) are defined by cytopenias, dysplastic morphology of blood and marrow cells, and clonal hematopoiesis, most individuals who acquire clonal hematopoiesis during aging will never develop MDS. Therefore, acquisition of somatic mutations that drive clonal expansion in the absence of cytopenias and dysplastic hematopoiesis can be considered clonal hematopoiesis of indeterminate potential (CHIP), analogous to monoclonal gammopathy of undetermined significance and monoclonal B-cell lymphocytosis, which are precursor states for hematologic neoplasms but are usually benign and do not progress. Because mutations are frequently observed in healthy older persons, detection of an MDS-associated somatic mutation in a cytopenic patient without other evidence of MDS may cause diagnostic uncertainty. Here we discuss the nature and prevalence of CHIP, distinction of this state from MDS, and current areas of uncertainty regarding diagnostic criteria for myeloid malignancies.

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Ramdohr, Florian, Astrid Monecke, Madlen Jentzsch, Thomas Zehrfeld, Gudrun Borte, Sebastian Schwind, Georg-Nikolaus Franke, Klaus H. Metzeler, Uwe Platzbecker, and Vladan Vucinic. "Extramedullary Clonal Hematopoiesis with Indeterminate Potential." Clinical Lymphoma Myeloma and Leukemia 21, no. 9 (September 2021): e696-e698. http://dx.doi.org/10.1016/j.clml.2021.04.008.

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Libby, Peter, and Benjamin L. Ebert. "CHIP (Clonal Hematopoiesis of Indeterminate Potential)." Circulation 138, no. 7 (August 14, 2018): 666–68. http://dx.doi.org/10.1161/circulationaha.118.034392.

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Testa, Ugo, Germana Castelli, and Elvira Pelosi. "CLONAL HEMATOPOIESIS: ROLE IN HEMATOLOGIC NON-HEMATOLOGIC." Mediterranean Journal of Hematology and Infectious Diseases 14, no. 1 (August 27, 2022): e2022069. http://dx.doi.org/10.4084/mjhid.2022.069.

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Hematopoietic stem cells (HSCs) ensure the coordinated and balanced production of all hematopoietic cell types throughout life. Aging is associated with a gradual decline of the self-renewal and regenerative potential of HSCs and with the development of clonal hematopoiesis. Clonal hematopoiesis of indeterminate potential (CHIP) is a term defining the clonal expansion of genetically variant hematopoietic cells bearing one or more gene mutations and/or structural variants (such as copy number alterations). CHIP increases exponentially with age and is associated with cancers, including hematologic neoplasia, cardiovascular and other diseases. The presence of CHIP consistently increases the risk of hematologic malignancy, particularly in individuals who have CHIP in association with peripheral blood cytopenia. Key words: hematopoiesis, hematopoietic stem cells, clonal hematopoiesis, gene mutations, next generation sequencing.

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Nardi, Valentina, Frank C. Kuo, and Robert P. Hasserjian. "Premalignant Clonal Hematopoietic Proliferations." American Journal of Clinical Pathology 152, no. 3 (July 15, 2019): 347–58. http://dx.doi.org/10.1093/ajcp/aqz079.

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AbstractObjectivesThe 2017 Workshop of the Society for Hematopathology/European Association for Hematopathology aimed to review premalignant clonal hematopoietic proliferations.MethodsThe workshop panel reviewed 27 cases of clonal proliferations of indeterminate significance or potential (18 myeloid, nine lymphoid) and rendered consensus diagnoses.ResultsImmunophenotyping and genetic studies on peripheral blood, bone marrow, and lymph node samples have led to the incidental detection of small clonal populations in asymptomatic individuals. These premalignant clonal myeloid and lymphoid proliferations include monoclonal gammopathy of uncertain significance, monoclonal B-cell lymphocytosis, in situ follicular neoplasia, in situ mantle cell neoplasia, clonal hematopoiesis of indeterminate potential, and clonal cytopenia of undetermined significance.ConclusionsCurrent diagnostic criteria for the diagnoses of premalignant clonal hematopoietic proliferations are reviewed and discussed in the context of the cases presented at the workshop.

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Chen, Sisi, and Yan Liu. "p53 involvement in clonal hematopoiesis of indeterminate potential." Current Opinion in Hematology 26, no. 4 (July 2019): 235–40. http://dx.doi.org/10.1097/moh.0000000000000509.

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Aviv, Abraham, and Daniel Levy. "Hemothelium, Clonal Hematopoiesis of Indeterminate Potential, and Atherosclerosis." Circulation 139, no. 1 (January 2, 2019): 7–9. http://dx.doi.org/10.1161/circulationaha.118.038434.

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Lyasnikova, E. A., L. Yu Ivanchenko, S. N. Kozlova, M. Yu SITNIKOVA, A. A. Kostareva, and E. V. Shlyakhto. "Clonal hematopoiesis of indeterminate potential and heart failure." Russian Journal of Cardiology 29, no. 11S (June 26, 2024): 6016. https://doi.org/10.15829/1560-4071-2024-6016.

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Modern studies demonstrate that clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor for the development and prognosis of heart failure (HF) of various origin. The pathophysiology and consequences of CHIP are gene-specific. The mechanisms involved in this process are complex and indicate the central role of systemic and myocardial inflammation, including the immune response dependent on the inflammasome/interleukin-1β/interleukin-6 cascade. CHIP and associated inflammatory pathways represent a powerful potential target, which rationales the research in the area of various HF stages and markers of this genetic phenomenon. A better understanding of the interactions between mutant clones, immune pathways, chronic inflammation and clinical implementation in HF may be important in the context of precision and personalized medicine.

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Sleptsov, A. A., M. S. Nazarenko, and V. Р. Puzyrev. "Common in atherogenesis and carcinogenesis: clonal hematopoiesis." Russian Journal of Cardiology 28, no. 10 (July 17, 2023): 5511. http://dx.doi.org/10.15829/1560-4071-2023-5511.

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Clonal hematopoiesis is a common age-dependent state accompanied by the expansion of mutant hematopoietic stem cells as a result of somatic mutations and is associated with a high risk of hematopoietic neoplasms and cardiovascular diseases. Clonal hematopoiesis in human ontogenesis occurs asymptomatically, and the fraction of mutant clones can exceed more than 2% of the total pool of circulating nucleated blood cells by age 70. Due to the variability of the accumulation rate of mutant clones, signs of clonal hematopoiesis can be observed at a younger age. Clonal hematopoiesis may act as a benign, precancerous condition and a strong factor for acute cardiovascular events such as myocardial infarction and stroke. Current evidence indicates that somatic mutations in driver genes of clonal hematopoiesis significantly increase the risk of acute conditions such as acute myeloid leukemia and acute myocardial infarction. The high mortality and morbidity of cardiovascular and cancer diseases, and their strong association with clonal hematopoiesis, make it of indeterminate potential worthy of close attention.

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Niño, Katia E., and Eric M. Pietras. "TNF Receptors Choose HSC Fate in Supporting Dnmt3a-Mutant Clonal Hematopoiesis." Cancer Discovery 12, no. 12 (December 2, 2022): 2724–26. http://dx.doi.org/10.1158/2159-8290.cd-22-1022.

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Summary: TNFα receptor signaling distinctly promotes self-renewal and lymphoid differentiation in Dnmt3a-mutant hematopoietic stem cells, contributing to clonal hematopoiesis of indeterminate potential. See related article by SanMiguel et al., p. 2763 (3).

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Bou Zerdan, Maroun, Lewis Nasr, Ludovic Saba, Paul Meouchy, Nadine Safi, Sabine Allam, Jenish Bhandari, and Chakra P. Chaulagain. "A Synopsis Clonal Hematopoiesis of Indeterminate Potential in Hematology." Cancers 14, no. 15 (July 28, 2022): 3663. http://dx.doi.org/10.3390/cancers14153663.

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Clonal hematopoiesis of indeterminate potential can be defined as genetic mutations that correlate in hematologic neoplasia such as myelodysplastic syndrome. Patients with cytopenia increasingly undergo molecular genetic tests of peripheral blood or bone marrow for diagnostic purposes. Recently, a new entity has been demarcated to lessen the risk of incorrect diagnoses of hematologic malignancies. This new entity is a potential precursor of myeloid diseases, analogous to monoclonal gammopathy of undetermined significance as a potential precursor of multiple myeloma.

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Büttner, P., J. Böttner, K. Krohn, R. Baber, U. Platzbecker, M. Cross, H. Thiele, and D. Branzan. "Clonal hematopoiesis of indeterminate potential in peripheral artery disease." Atherosclerosis 355 (August 2022): 2. http://dx.doi.org/10.1016/j.atherosclerosis.2022.06.093.

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Lee, Man K. S., Dragana Dragoljevic, Camilla Bertuzzo Veiga, Nan Wang, Laurent Yvan-Charvet, and Andrew J. Murphy. "Interplay between Clonal Hematopoiesis of Indeterminate Potential and Metabolism." Trends in Endocrinology & Metabolism 31, no. 7 (July 2020): 525–35. http://dx.doi.org/10.1016/j.tem.2020.02.005.

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Khetarpal, Sumeet A., Arman Qamar, Alexander G. Bick, José J. Fuster, Sekar Kathiresan, Siddhartha Jaiswal, and Pradeep Natarajan. "Clonal Hematopoiesis of Indeterminate Potential Reshapes Age-Related CVD." Journal of the American College of Cardiology 74, no. 4 (July 2019): 578–86. http://dx.doi.org/10.1016/j.jacc.2019.05.045.

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Chen, Jianchun, Caitlyn Vlasschaert, Cassianne Robinson-Cohen, Bryan R. Kestenbaum, Ming-Zhi Zhang, and Raymond C. Harris. "Clonal Hematopoiesis of Indeterminate Potential Associates with Severe AKI." Journal of the American Society of Nephrology 34, no. 11S (November 2023): 772–73. http://dx.doi.org/10.1681/asn.20233411s1772d.

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Vlasschaert, Caitlyn, Bryan R. Kestenbaum, Samuel A. Silver, Jianchun Chen, Elvis A. Akwo, Pavan K. Bhatraju, Ming-Zhi Zhang, et al. "Clonal Hematopoiesis of Indeterminate Potential Is Associated with AKI." Journal of the American Society of Nephrology 34, no. 11S (November 2023): 432. http://dx.doi.org/10.1681/asn.20233411s1432a.

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Brogan, James, Ashwin Kishtagari, Robert W. Corty, Yash Pershad, Brian Sharber, Yaomin Xu, and Alexander G. Bick. "Incidence of Cytopenia in Clonal Hematopoiesis of Indeterminate Potential." Blood 144, Supplement 1 (November 5, 2024): 5637. https://doi.org/10.1182/blood-2024-205713.

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Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a risk factor for myeloid neoplasms (MN) and multiple other diseases of aging. CHIP with concurrent cytopenia is a five-fold stronger risk factor for these diseases. However, the incidence of cytopenia in individuals with CHIP is not well-described. We quantify the incidence of cytopenia among 9,278 individuals with CHIP across three cohorts and identify risk factors for cytopenia among these individuals. Methods: Participants with genome sequencing from the All of Us Research Program (AoU) and Vanderbilt BioVU biorepository, and exome sequencing from UK Biobank (UKB), were screened for CHIP using Mutect2 to identify somatic mutations in canonical driver genes (Vlasschaert et al. Blood 2023). Survival analysis was conducted to compare the risk of developing a persistent cytopenia in participants with CHIP and matched controls using hematologic laboratory values, demographic variables, CHIP driver genes, and clone size as covariates. Participants were included if they had multi-timepoint complete blood count (CBC) data without evidence of a cytopenia or MN prior to sequencing. Cytopenia was defined as two observations of hemoglobin < 12.0 g/dL (females) or 13.0 g/dL (males), platelets < 150,000 cells/µL, or white blood cell count < 3,700 cells/µL at least 120 days apart without an intervening normal measurement. Participants with CHIP were matched 1:3 with controls on age, sex, and smoking status. The follow-up period commenced at the date of sequencing and terminated at the earliest occurrence of incident cytopenia, MN, or last CBC. Results: Sequencing data were available for 852,639 participants. A total of 168,428 participants, including 9,279 with CHIP, met inclusion criteria. The final case-control cohort contained 9,278 cases and 24,758 matched controls. Median time at risk was 2.28 years [interquartile range: 1.41 - 2.89] in AoU, 3.51 years [1.16 - 7.73] in BioVU and 5.94 years [4.76 - 6.72] in UKB. Incident cytopenia occurred in 1,235 cases (13.3%) and 2,839 controls (11.5%), showing a statistically significant difference across all three cohorts (HRAoU = 1.16, 95% confidence interval: [1.01 - 1.34], P=0.04; HRBioVU = 1.17 [1.04 - 1.31], P<0.01; HRUKB = 1.19 [1.08 - 1.32], P<0.01). In BioVU and UKB, risk factors for incident cytopenia included male sex, age ≥ 65, mean corpuscular volume ≥ 100, red cell distribution width ≥ 15, ≥ 2 CHIP mutations, or a high-risk mutation (in SRSF2, SF3B1, ZRSR2, IDH1, IDH2, FLT3, RUNX1, JAK2). In AoU, only male sex and RDW ≥ 15 conferred increased risk of cytopenia. Individuals with multiple of these risk factors had a significantly greater risk of incident cytopenia. For example, BioVU participants with CHIP and no risk factors had an 8% incidence of cytopenia at 2 years. This increased to 20% among participants with 2 or 3 risk factors and 40% among participants with 4 or 5 risk factors. Participants with CHIP and incident cytopenia had significantly higher rates of subsequent MN compared to those without cytopenia across all three cohorts (HRAoU = 4.68, 95% confidence interval: [2.12 - 10.30], P<0.01; HRBioVU = 2.63 [1.67 - 4.13], P<0.01; HRUKB = 6.70 [4.07 - 11.03], P<0.01). Conclusion: Longitudinal analysis of 9,278 participants with CHIP across three cohorts demonstrated significantly higher incidence of cytopenia in participants with CHIP than matched controls and identified risk factors for developing a persistent cytopenia. Our results enable longitudinal risk stratification and personalized risk prediction among individuals with CHIP. Identifying individuals at the highest risk of developing cytopenia and subsequent MN will inform the design of interventional CHIP clinical trials.

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Ganuza, Miguel, Trent Hall, David Finkelstein, Yong-Dong Wang, Ashley Chabot, Guolian Kang, Wenjian Bi, Gang Wu, and Shannon McKinney-Freeman. "The global clonal complexity of the murine blood system declines throughout life and after serial transplantation." Blood 133, no. 18 (May 2, 2019): 1927–42. http://dx.doi.org/10.1182/blood-2018-09-873059.

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Abstract Although many recent studies describe the emergence and prevalence of “clonal hematopoiesis of indeterminate potential” in aged human populations, a systematic analysis of the numbers of clones supporting steady-state hematopoiesis throughout mammalian life is lacking. Previous efforts relied on transplantation of “barcoded” hematopoietic stem cells (HSCs) to track the contribution of HSC clones to reconstituted blood. However, ex vivo manipulation and transplantation alter HSC function and thus may not reflect the biology of steady-state hematopoiesis. Using a noninvasive in vivo color-labeling system, we report the first comprehensive analysis of the changing global clonal complexity of steady-state hematopoiesis during the natural murine lifespan. We observed that the number of clones (ie, clonal complexity) supporting the major blood and bone marrow hematopoietic compartments decline with age by ∼30% and ∼60%, respectively. Aging dramatically reduced HSC in vivo–repopulating activity and lymphoid potential while increasing functional heterogeneity. Continuous challenge of the hematopoietic system by serial transplantation provoked the clonal collapse of both young and aged hematopoietic systems. Whole-exome sequencing of serially transplanted aged and young hematopoietic clones confirmed oligoclonal hematopoiesis and revealed mutations in at least 27 genes, including nonsense, missense, and deletion mutations in Bcl11b, Hist1h2ac, Npy2r, Notch3, Ptprr, and Top2b.

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Schenck, Ryan O., Niels A. Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, and Alexander R. Anderson. "Abstract 634: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks." Cancer Research 82, no. 12_Supplement (June 15, 2022): 634. http://dx.doi.org/10.1158/1538-7445.am2022-634.

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Abstract Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning method that allows us to diagnose CHIP without DNA sequencing. This method allows for the identification of patients who may have CH driven by structural variants such as copy number variants. We use this method to examine a cohort of 656 normal patients without evidence of CHIP based on mutation showing that we identify the presence of CHIP roughly a third of these patients. Clonal hematopoiesis is driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates for stim cell numbers differing by orders of magnitude.Finally, using a mechanistic model of clonal hematopoeisis and fCpGs we examine the temporal ability to diagnose CHIP given single and multiple expanding clones. We illustrate that multiple driver mutations within the same clone leads to an increased detection ability with an increased expansion rate (i.e. fitness) and in cases where drivers are found in separate, competing clones. Citation Format: Ryan O. Schenck, Niels A. Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential using fluctuating methylation clocks [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 634.

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Olkhovskiy, I. A., J. G. Garber, A. S. Gorbenko, M. A. Stolyar, O. M. Miller, E. S. Kostina, Yu Yu Komarovskiy, and V. V. Potilitsina. "JAK2V617F-positive clonal hematopoiesis of indeterminate potential in pregnant women." Obstetrics, Gynecology and Reproduction 13, no. 3 (September 21, 2019): 204–10. http://dx.doi.org/10.17749/2313-7347.2019.13.3.204-210.

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Aim: to assess the prevalence of V617F somatic mutation of the JAK2 gene in pregnant women.Materials and methods. This non-interventional study was performed in the framework of routine clinical practice and included 1532 samples of venous blood from pregnant women who applied for medical assistance at Krasnoyarsk Regional Clinical Center for Maternal and Child Welfare. We used blood samples left after all routine laboratory tests had been done. These leftovers were pooled in the way that ensured an equal ratio of nucleated cells. Each pool contained 7 separate blood samples. The unused samples that remained after the pooling were frozen and stored at –20°C until the end of entire testing procedure. The V617F JAK2 mutation was detected by the real-time allele-specific polymerase chain reaction test.Results. Among the examined pregnant women, 6 (0.4 %) were identified as carriers of V617F JAK2 mutation. Three women with this mutation suffered from infertility for 4, 5, and 10 years; two of them had repeated miscarriages in the first trimester of pregnancy. The 6 women – carriers of this mutations had no concomitant genetic polymorphisms typical of thrombophilia (factors FII, FV), and no abnormal coagulation characteristics. Analysis of their medical records showed that in the past, two of these women had gestational hypertension, one developed a clinical picture of preeclampsia, and another one (with the maximum presence of the mutant allele) had a history of acute lymphoblastic leukemia followed by stable remission.Conclusion. The routine laboratory detection of the V617F JAK2 mutation can facilitate timely identification of the increased risk of pregnancy pathology, as well as timely diagnosis of hematological cancer.

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Takahashi, Koichi, Feng Wang, Hagop Kantarjian, Xingzhi Song, Keyur Patel, Sattva Neelapu, Curtis Gumbs, et al. "Copy number alterations detected as clonal hematopoiesis of indeterminate potential." Blood Advances 1, no. 15 (June 19, 2017): 1031–36. http://dx.doi.org/10.1182/bloodadvances.2017007922.

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Veiga, Camilla Bertuzzo, Erin M. Lawrence, Andrew J. Murphy, Marco J. Herold, and Dragana Dragoljevic. "Myelodysplasia Syndrome, Clonal Hematopoiesis and Cardiovascular Disease." Cancers 13, no. 8 (April 19, 2021): 1968. http://dx.doi.org/10.3390/cancers13081968.

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The development of myelodysplasia syndromes (MDS) is multiphasic and can be driven by a plethora of genetic mutations and/or abnormalities. MDS is characterized by a hematopoietic differentiation block, evidenced by increased immature hematopoietic cells, termed blast cells and decreased mature circulating leukocytes in at least one lineage (i.e., cytopenia). Clonal hematopoiesis of indeterminate potential (CHIP) is a recently described phenomenon preceding MDS development that is driven by somatic mutations in hemopoietic stem cells (HSCs). These mutant HSCs have a competitive advantage over healthy cells, resulting in an expansion of these clonal mutated leukocytes. In this review, we discuss the multiphasic development of MDS, the common mutations found in both MDS and CHIP, how a loss-of-function in these CHIP-related genes can alter HSC function and leukocyte development and the potential disease outcomes that can occur with dysfunctional HSCs. In particular, we discuss the novel connections between MDS development and cardiovascular disease.

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Saygin, Caner, and Lucy A. Godley. "Genetics of Myelodysplastic Syndromes." Cancers 13, no. 14 (July 6, 2021): 3380. http://dx.doi.org/10.3390/cancers13143380.

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Myelodysplastic syndrome (MDS) describes a heterogeneous group of bone marrow diseases, now understood to reflect numerous germline and somatic drivers, characterized by recurrent cytogenetic abnormalities and gene mutations. Precursor conditions including clonal hematopoiesis of indeterminate potential and clonal cytopenia of undetermined significance confer risk for MDS as well as other hematopoietic malignancies and cardiovascular complications. The future is likely to bring an understanding of those individuals who are at the highest risk of progression to MDS and preventive strategies to prevent malignant transformation.

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Gaulin, Charles, Katalin Kelemen, and Cecilia Arana Yi. "Molecular Pathways in Clonal Hematopoiesis: From the Acquisition of Somatic Mutations to Transformation into Hematologic Neoplasm." Life 12, no. 8 (July 28, 2022): 1135. http://dx.doi.org/10.3390/life12081135.

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Hematopoietic stem cell aging, through the acquisition of somatic mutations, gives rise to clonal hematopoiesis (CH). While a high prevalence of CH has been described in otherwise healthy older adults, CH confers an increased risk of both hematologic and non-hematologic diseases. Classification of CH into clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS) further describes this neoplastic myeloid precursor state and stratifies individuals at risk of developing clinically significant complications. The sequential acquisition of driver mutations, such as DNMT3A, TET2, and ASXL1, provide a selective advantage and lead to clonal expansion. Inflammation, microbiome signatures, and external selective pressures also contribute to clonal evolution. Despite significant progress in recent years, the precise molecular mechanisms driving CH transformation to hematologic neoplasms are not well defined. Further understanding of these complex mechanisms may improve risk stratification and introduce therapeutic interventions in CH. Here we discuss the genetic drivers underpinning CH, mechanisms for clonal evolution, and transformation to hematologic neoplasm.

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Hoermann, Gregor, Georg Greiner, Andrea Griesmacher, and Peter Valent. "Clonal Hematopoiesis of Indeterminate Potential: A Multidisciplinary Challenge in Personalized Hematology." Journal of Personalized Medicine 10, no. 3 (August 20, 2020): 94. http://dx.doi.org/10.3390/jpm10030094.

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Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition that represents a potential pre-phase of hematologic neoplasm. Next-generation sequencing (NGS) is used to detect and monitor clonal hematopoiesis, and the spectrum of mutations substantially overlaps with that of myeloid neoplasms with DNMT3A, TET2, ASXL1, and JAK2 being the most frequently mutated. While, in general, the risk of progression to an overt myeloid neoplasm is only modest, the progression risk increases in patients with unexplained cytopenia or multiple mutations. In addition, CHIP represents a previously unrecognized major risk factor for atherosclerosis and cardiovascular disease (CVD), including coronary heart disease, degenerative aortic valve stenosis, and chronic heart failure; and a causative role of CHIP in the development of CVD has been demonstrated in vitro and in vivo. The management of patients with CHIP is a rapidly emerging topic in personalized medicine, as NGS has become widely available for clinical medicine. It requires a highly multidisciplinary setting, including hematology/oncology, cardiology, (clinical) pathology, and genetics for individualized guidance. Further research is urgently needed to provide robust evidence for future guidelines and recommendations on the management of patients with CHIP in the era of personalized medicine.

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Sorscher, Steven. "Letter to the Editor: Significance of Clonal Hematopoiesis of Indeterminate Potential." Journal of the National Comprehensive Cancer Network 16, no. 9 (September 2018): 1032–33. http://dx.doi.org/10.6004/jnccn.2018.7075.

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Dufossée, Mélody, Séverine Marti, Sami Fawaz, David-Alexandre Trégouët, Christophe Tzourio, Stéphanie Debette, Chloé James, Thierry Couffinhal, and Olivier Mansier. "Clonal hematopoiesis of indeterminate potential: A cardiovascular risk factor among others." Archives of Cardiovascular Diseases Supplements 14, no. 2 (June 2022): 147. http://dx.doi.org/10.1016/j.acvdsp.2022.04.008.

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Sebastian, Kimberley N., Hatice Gülçin Özer, Cory Howard, Laura Chadsey, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, et al. "Abstract 1620: Clonal hematopoiesis of indeterminate potential in the companion dog." Cancer Research 82, no. 12_Supplement (June 15, 2022): 1620. http://dx.doi.org/10.1158/1538-7445.am2022-1620.

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Abstract Background: Clonal hematopoiesis of indeterminate potential (CHIP) is a clinical entity of aging humans that is characterized by cancer-associated mutations in white blood cells, without evidence of overt neoplasia. CHIP has been associated with an increased risk of hematologic cancers, cardiovascular disease, and all-cause mortality. We hypothesized that somatic mutations in specific genes associated with human CHIP would be detectable in the blood of aged dogs not known to have hematologic disorders. Methods: DNA from paired germline and whole blood samples from 93 geriatric canine patients affected by solid cancer were subjected to targeted next generation sequencing. Impact of the variants was predicted using Polymorphism Phenotyping version 2 software (PolyPhen-2, Harvard). Clinical and demographic data were extracted from medical records. Results: Somatic variants were detected in peripheral blood of four (4.3%) female dogs aged 12-15 years. Affected genes were ASXL1, KIT, SF3B1, TET2, RUNX1, and PPM1D. The variant in PPM1D was a nonsense mutation, while the other five variants were single nucleotide non-synonymous variants in protein coding regions of the genes. Following analysis by PolyPhen-2, the single nucleotide variants in KIT and SF3B1 were predicted to be benign, while the variants in ASXL1, TET2, and RUNX1 were predicted to be damaging. Conclusion: These results support the presence of variants in CHIP-associated genes in geriatric canids at a frequency similar to that observed in people, and the dog represents the first species in which the genetic lesion of CHIP has been documented. Further investigations are needed to confirm the association of this genetic lesion with clinical outcomes. Citation Format: Kimberley N. Sebastian, Hatice Gülçin Özer, Cory Howard, Laura Chadsey, Arletta Lozanski, Tzyy-Jye Doong, Gerard Lozanski, Wenjuan Ma, William C. Kisseberth, John C. Byrd, Bonnie K. Harrington. Clonal hematopoiesis of indeterminate potential in the companion dog [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1620.

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Sella, Tal, Geoffrey Fell, Peter Grant Miller, Christopher James Gibson, Shoshana M. Rosenberg, Craig Snow, Daniel G. Stover, et al. "Testing for clonal hematopoiesis of indeterminate potential in breast cancer survivors." Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021): e24108-e24108. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.e24108.

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e24108 Background: Clonal hematopoiesis of Indeterminate Potential (CHIP) is associated with adverse clinical outcomes including increased risk of hematologic malignancies and heart disease. Limited data suggest an increased prevalence of CHIP in patients treated for solid tumors, particularly after exposure to radiation and chemotherapy. CHIP testing may inform risk-reduction strategies for cancer survivors. Little is known about patient knowledge, attitudes, and preferences regarding CHIP testing. Methods: We surveyed survivors without history of recurrence participating in an ongoing prospective cohort study of young women with breast cancer (BC). The survey was sent by email and included an introduction to CHIP including risk factors and clinical associations. Respondents then reviewed a vignette and were asked about CHIP testing preferences (definitely/probably test vs. definitely/probably not test) considering sequentially: 1) population-based 10-year risk of BC recurrence, hematological malignancy and heart disease; 2) estimated increase in these risks with CHIP; 3) current CHIP management; 4) a dedicated CHIP clinic; and 5) a theoretical CHIP treatment. Changes in preferences from the prior scenario were evaluated with the McNemar's test using a type I error rate of 5%. Results: 528/642 (82.2%) eligible women responded to the survey, at a median age of 46 (range: 31-54) years (median time from diagnosis: 108 months (range: 60-168)), and 88% were white. Most had stage 1/2 BC (78.8%) and had received chemotherapy (73.1%) and/or radiation (61.9%). 93.6% had never heard of CHIP prior to survey. After initial patient vignette presentation, most women (87.1%,) recommended CHIP testing if offered. Preferences for testing decreased (p<0.05) when considering population-based risks, with 11.1% shifting their preference from CHIP testing to not testing. After considering increased risks associated with CHIP, interest in testing increased (p<0.05), with 10.1% shifting their preference to testing. Interest significantly (p<0.05) increased with the possibility of managing CHIP through a clinic or a hypothetical CHIP treatment, with 7.2% and 14.1% switching their preferences towards testing, respectively. Finally, 75.8% responded that they themselves, after learning about CHIP and reviewing the vignette, would want to have CHIP testing; 28.2% reported that learning about CHIP and the associated risks caused them at least moderate anxiety. Conclusion: Few young BC survivors were aware of CHIP yet most indicated an interest in testing after learning about it. Testing preferences were influenced by risks presented and potential management strategies. Findings highlight the importance of effective risk communication and the need for adequate psychosocial support when considering testing for CHIP and other potential clinical biomarkers predictive of cancer and other medical risks in cancer survivors.

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Huang, Yi-Chun, and Chao-Yung Wang. "Telomere Attrition and Clonal Hematopoiesis of Indeterminate Potential in Cardiovascular Disease." International Journal of Molecular Sciences 22, no. 18 (September 13, 2021): 9867. http://dx.doi.org/10.3390/ijms22189867.

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Clinical evidence suggests that conventional cardiovascular disease (CVD) risk factors cannot explain all CVD incidences. Recent studies have shown that telomere attrition, clonal hematopoiesis of indeterminate potential (CHIP), and atherosclerosis (telomere–CHIP–atherosclerosis, TCA) evolve to play a crucial role in CVD. Telomere dynamics and telomerase have an important relationship with age-related CVD. Telomere attrition is associated with CHIP. CHIP is commonly observed in elderly patients. It is characterized by an increase in blood cell clones with somatic mutations, resulting in an increased risk of hematological cancer and atherosclerotic CVD. The most common gene mutations are DNA methyltransferase 3 alpha (DNMT3A), Tet methylcytosine dioxygenase 2 (TET2), and additional sex combs-like 1 (ASXL1). Telomeres, CHIP, and atherosclerosis increase chronic inflammation and proinflammatory cytokine expression. Currently, their epidemiology and detailed mechanisms related to the TCA axis remain incompletely understood. In this article, we reviewed recent research results regarding the development of telomeres and CHIP and their relationship with atherosclerotic CVD.

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Patel, Jay L. "The Clinical and Laboratory Features of Clonal Hematopoiesis of Indeterminate Potential." Advances in Molecular Pathology 1, no. 1 (November 2018): 37–42. http://dx.doi.org/10.1016/j.yamp.2018.06.005.

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Durrani, Jibran, Hassan Awada, Ashwin Kishtagari, Cassandra M. Kerr, Vera Adema, Yasunobu Nagata, Teodora Kuzmanovic, et al. "Large Granular Lymphocytic Leukemia Coexists with Clonal Hematopoiesis of Indeterminate Potential." Blood 134, Supplement_1 (November 13, 2019): 3743. http://dx.doi.org/10.1182/blood-2019-129330.

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Large granular lymphocytic leukemia (LGL) is a lymphoproliferative cytotoxic T cell (CTL) that typically presents in elderly population. The spectrum of the disease ranges from semi-reactive oligoclonal to clonal CTL expansion, and from silent to a chronic leukemia with para-neoplastic manifestation. However the description of the disease still preceded the new genetic landscape mapping techniques. In lieu of this, we analyzed the genetic landscape of LGL using a set of 33 genes. Interestingly, not only did the deeper analysis help with a better understanding of the complex CTL proliferative processes but indicated a suspected association with conditions such as clonal hematopoiesis of indeterminate potential (CHIP). Association of LGL with age related CH has been described in the past by us and others. Our results indicate that LGL is often associated with the presence of myeloid mutations, generally consistent with the most common typical CHIP mutations (DNMT3A, TET2, ASXL1). We then analyzed a set of 13 patients with coexistent MDS/LGL. This observation raises the question that LGL is, at least in some cases, a tumor surveillance response. All LGL patients were diagnosed using a stringent single center diagnostic criteria and at the time of diagnosis, were also checked for other conditions including MDS to prevent any risks of overlooked diagnoses. A previously well described diagnostic standard of >3/5 positive criteria was used; (i) presence of large granular lymphocytes (>500/μL, by differential counts from complete blood count) for >6 months; (ii) abnormal cytotoxic T lymphocytes expressing CD2, CD56 and CD57 and lacking CD28; (iii) preferential usage of a TCR Vβ family by flow cytometry; and (iv) TCR gene rearrangement by PCR; (v) bone marrow infiltration with LGL is another diagnostic criterion but a designated marrow biopsy is often not performed in clear LGL which are otherwise asymptomatic. Coexistent presence of MDS and LGL was confirmed in 13/240 (5%) of the patients. These patients displayed typical features of MDS including abnormal cytogenetics (8/13), dysmorphia of myeloid cells in the bone marrow (13/13), ringed sideroblasts (1/13) and the presence of highly clonal somatic myeloid mutations (8/13) with an average VAF of 28+3%. When compared to LGL only, the MDS/LGL series had 15% vs. 39% (P=0.014) STAT3/5b mutations. We detected the presence of mutant myeloid clones in 25% (41/161) of the patients with pure LGL with an average VAF of 35+ 2%. Suspecting that these mutations may be present early in MDS and CHIP, we compared the mutational spectrum of LGL against MDS (n=835) and CHIP. Indeed, an overlap between the typical CHIP mutations was noted with LGL; in addition the clonal burden in CHIP was observed to be lower, 13% vs. 33% in LGL indicating a more advanced myeloid disease in LGL. This could be due to overlapping demographics or through a common pathophysiologic link. Spliceosomal mutations, cohesion complex, PRC2 and RAS mutations were overrepresented in MDS and CHIP in comparison to LGL. Our results indicate that LGL is often associated with myeloid mutations that are also typical in CHIP. Though, age-related changes or other mutagenic stressors, including inflammatory changes could be contributing factors to both LGL and CHIP outgrowth, conversely LGL may evolve as a consequence of a tumor surveillance response to myeloid neoplasms or CHIP. While the coexistence of MDS and LGL has been described in the past, and our analysis corroborates this, we observed that LGL may also coexist with CHIP in some patients. The implication of this would be beneficial to our understanding of, not only, the individual diseases but could also impact care in CHIP survivorship. Disclosures Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Tolero, Karyopharma: Honoraria; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Novartis: Consultancy; Alexion: Consultancy.

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Conces, Madison, Ying Ni, Peter Bazeley, Bhumika Patel, Pauline Funchain, and Hetty E. Carraway. "Clonal hematopoiesis of indeterminate potential (CHIP) mutations in solid tumor malignancies." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 1507. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.1507.

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1507 Background: CHIP predisposes to a higher risk of developing hematological malignancies and cardiac events. Multiple germline mutations have been recognized as contributing to CHIP, most notably ASXL1, DNMT3A, and TET2. The frequency of CHIP mutations in solid tumor malignancies (STM) is unknown. We report the frequency and incidence of CHIP mutations in adult patients (pts) with STM. Methods: Data from 880 pts with STM who underwent next generation sequencing (NGS) at Foundation One from 2013-2017 was collected. This excluded two pts with known primary hematological malignancies who were removed. A list of CHIP mutations using NCCN guidelines as well as numerous original research articles was created, and tabulation of pathogenic or likely pathogenic mutations ( ASXL1, DNMT3A, TET2, JAK2, SF3B1, TP53, GNAS, N/KRAS) was performed. To date, only the lung, breast, and colorectal cancer pts have been annotated (N = 372) since these cancers have an overall higher incidence and prevalence in society. Results: Annotation of lung cancer pts (155/880), breast (118/880), and colorectal cancer pts (99/880) is collected and represents about 40% of all pts. At least one CHIP mutation was present in 44.5% (69/155) lung cancer pts, 32.2% (38/118) in breast cancer pts, and 7.1% (7/99) in colorectal cancer pts. Most common mutations found were TP53 and KRAS at 29.6% (110/372) and 28.0% (104/372), respectively. Mutations in genes not known to be somatic drivers for solid tumor malignancies, particularly SF3B1, DNMT3A, and JAK2, were found at very low frequencies 0.8% (3/372), 0.5% (2/372), and 0.3% (1/372), respectively. Notably, ASXL1 and TET2 mutations were not encountered in any pts. Conclusions: In tumor NGS testing, multiple CHIP mutations were noted to be present within the cohort of lung, breast, and colorectal cancers. There is a need to further understand clinical consequences of CHIP mutations incidentally found in pts with STM given known clinical implications of CHIP. We will report on clinical data (comorbidities), response/non-response to therapy, and identify specific molecular patterns of mutations to further understand the role of CHIP in pts with STM.

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Malcovati, Luca, and Mario Cazzola. "The shadowlands of MDS: idiopathic cytopenias of undetermined significance (ICUS) and clonal hematopoiesis of indeterminate potential (CHIP)." Hematology 2015, no. 1 (December 5, 2015): 299–307. http://dx.doi.org/10.1182/asheducation-2015.1.299.

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AbstractThe WHO classification provides the best diagnostic approach to myelodysplastic syndromes (MDS). However, biologic and analytic limitations have emerged in the criteria currently adopted to establish the diagnosis and to classify MDS. The provisional category of idiopathic cytopenia of undetermined significance (ICUS) has been proposed to describe patients in whom MDS is possible but not proven. To formulate a diagnosis of ICUS, a thorough diagnostic work-up is required and repeated tests should be performed to reach a conclusive diagnosis. Recent studies provided consistent evidence of age-related hematopoietic clones (clonal hematopoiesis of indeterminate potential; CHIP), driven by mutations of genes that are recurrently mutated in myeloid neoplasms and associated with increase in the risk of hematologic cancer. A subset of mutated genes, mainly involved in epigenetic regulation, are likely initiating lesions driving the expansion of a premalignant clone. However, in a fraction of subjects the detected clone may be a small malignant clone expanding under the drive of the detected and additional undetected mutations. In addition, several experimental evidences suggest the potential relevance of an abnormal bone marrow environment in the selection and evolution of hematopoietic clones in MDS. The spreading of massively parallel sequencing techniques is offering translational opportunities in the clinical approach to myeloid neoplasms. Although several issues remain to be clarified, targeted gene sequencing may be of potential value in the dissection between clonal myelodysplasia, nonclonal cytopenia, and clonal hematopoiesis arising upon aging or in the context of acquired marrow failure.

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Soyfer, Eli M., and Angela G. Fleischman. "Inflammation in Myeloid Malignancies: From Bench to Bedside." Journal of Immunotherapy and Precision Oncology 4, no. 3 (July 14, 2021): 160–67. http://dx.doi.org/10.36401/jipo-21-3.

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ABSTRACT Myeloid malignancies, stemming from a somatically mutated hematopoietic clone, can cause a wide variety of clinical consequences, including pancytopenia in myelodysplastic syndrome, overproduction of three myeloid lineages in myeloproliferative neoplasm, and the rapid growth of immature hematopoietic cells in acute myeloid leukemia (AML). It is becoming clear that inflammation is a hallmark feature of clonal myeloid conditions, ranging from clonal hematopoiesis of indeterminate potential to AML. Fundamental findings from laboratory research on inflammation in myeloid malignancies has potential implications for diagnosis, prognostication, and treatment in these diseases. In this review, we highlighted some pertinent basic science findings regarding the role of inflammation in myeloid malignancies and speculated how these findings could impact the clinical care of patients.

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Lin, Amy E., Philipp J. Rauch, Siddhartha Jaiswal, and Benjamin L. Ebert. "Clonal Hematopoiesis: Confluence of Malignant and Nonmalignant Diseases." Annual Review of Cancer Biology 6, no. 1 (April 11, 2022): 187–200. http://dx.doi.org/10.1146/annurev-cancerbio-060121-120026.

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Clonal hematopoiesis of indeterminate potential (CHIP) is a state in which somatic mutations in hematopoietic stem cells lead to clonal expansion of blood cells in individuals without hematologic malignancy. The mutated genes, including TET2, DNMT3A, ASXL1, TP53, JAK2, and SF3B1, are also recurrently mutated in myeloid malignancies. Individuals with CHIP have an increased risk of developing a hematologic cancer. Moreover, individuals with CHIP have an elevated risk of all-cause mortality that is significantly attributable to cardiovascular disease, independent of traditional risk factors. The mechanism for this increased risk is likely linked to increased inflammation driven by mutated macrophages, in part through inflammasome activation. This has broadened our understanding of how chronic diseases are influenced by CHIP and of the mechanistic role of inflammation in these disorders.

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Busque, Lambert, Maxine Sun, Manuel Buscarlet, Sami Ayachi, Yassamin Feroz Zada, Sylvie Provost, Vincent Bourgoin, et al. "High-sensitivity C-reactive protein is associated with clonal hematopoiesis of indeterminate potential." Blood Advances 4, no. 11 (June 3, 2020): 2430–38. http://dx.doi.org/10.1182/bloodadvances.2019000770.

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Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is predictive of hematological cancers and cardiovascular diseases, but the etiology of CHIP initiation and clonal expansion is unknown. Several lines of evidence suggest that proinflammatory cytokines may favor mutated hematopoietic stem cell expansion. To investigate the potential link between inflammation and CHIP, we performed targeted deep sequencing of 11 genes previously implicated in CHIP in 1887 subjects aged >70 years from the Montreal Heart Institute Biobank, of which 1359 had prior coronary artery disease (CAD), and 528 controls did not. We assessed association of CHIP with log transformed high-sensitivity C-reactive protein (hs-CRP), a validated biomarker of inflammation. CHIP was identified in 427 of the 1887 subjects (22.6%). CHIP mutations were more frequently identified in DNMT3A (11.6%) and TET2 (6.1%), with a higher proportion of TET2 mutations occurring in controls than in patients with CAD (9.0% vs 4.9%, P < .001). CHIP carriers had 21% higher hs-CRP levels compared with their noncarrier counterparts (eβ = 1.21, 95% confidence interval [CI]: 1.08 to 1.36; P = .001). A similar effect was observed in the subgroup of patients with known CAD (eβ = 1.22, 95% CI: 1.06 to 1.41; P = .005). These findings confirm the association between inflammation and CHIP. This association may open investigational avenues aimed at documenting mechanisms linking inflammation to clonal progression and ultimately supports prevention interventions to attenuate CHIP’s impact on cardiovascular disease and cancer.

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Chavakis, Triantafyllos, Ben Wielockx, and George Hajishengallis. "Inflammatory Modulation of Hematopoiesis: Linking Trained Immunity and Clonal Hematopoiesis with Chronic Disorders." Annual Review of Physiology 84, no. 1 (February 10, 2022): 183–207. http://dx.doi.org/10.1146/annurev-physiol-052521-013627.

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Inflammation-adapted hematopoietic stem and progenitor cells (HSPCs) have long been appreciated as key drivers of emergency myelopoiesis, thereby enabling the bone marrow to meet the elevated demand for myeloid cell generation under various stress conditions, such as systemic infection, inflammation, or myelosuppressive insults. In recent years, HSPC adaptations were associated with potential involvement in the induction of long-lived trained immunity and the emergence of clonal hematopoiesis of indeterminate potential (CHIP). Whereas trained immunity has context-dependent effects, protective in infections and tumors but potentially detrimental in chronic inflammatory diseases, CHIP increases the risk for hematological neoplastic disorders and cardiometabolic pathologies. This review focuses on the inflammatory regulation of HSPCs in the aforementioned processes and discusses how modulation of HSPC function could lead to novel therapeutic interventions.

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Zhang, Qi, Rita Yim, Paul Lee, Lynn Chin, Vivian Li, and Harinder Gill. "Implications of Clonal Hematopoiesis in Hematological and Non-Hematological Disorders." Cancers 16, no. 23 (December 9, 2024): 4118. https://doi.org/10.3390/cancers16234118.

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Clonal hematopoiesis (CH) is associated with an increased risk of developing myeloid neoplasms (MNs) such as myelodysplastic neoplasm (MDS) and acute myeloid leukemia (AML). In general, CH comprises clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). It is an age-related phenomenon characterized by the presence of somatic mutations in hematopoietic stem cells (HSCs) and hematopoietic stem and progenitor cells (HSPCs) that acquire a fitness advantage under selection pressure. Individuals with CHIP have an absolute risk of 0.5–1.0% per year for progressing to MDS or AML. Inflammation, smoking, cytotoxic therapy, and radiation can promote the process of clonal expansion and leukemic transformation. Of note, exposure to chemotherapy or radiation for patients with solid tumors or lymphomas can increase the risk of therapy-related MN. Beyond hematological malignancies, CH also serves as an independent risk factor for heart disease, stroke, chronic obstructive pulmonary disease, and chronic kidney disease. Prognostic models such as the CH risk score and MN-prediction models can provide a framework for risk stratification and clinical management of CHIP/CCUS and identify high-risk individuals who may benefit from close surveillance. For CH or related disorders, therapeutic strategies targeting specific CH-associated mutations and specific selection pressure may have a potential role in the future.

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Schenck, Ryan O., Niels Asger Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, and Alexander R. A. Anderson. "Abstract A019: Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks." Cancer Research 82, no. 10_Supplement (May 15, 2022): A019. http://dx.doi.org/10.1158/1538-7445.evodyn22-a019.

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Abstract Clonal hematopoiesis (CH), such as clonal hematopoiesis of indeterminant potential (CHIP), is diagnosed based on somatic genomic alterations in the absence of hematologic malignancy. At present, CHIP is diagnosed using peripheral blood, where putative driver point mutations and small insertions/deletions whose variant allele frequency is greater or equal to two percent. Generally, the prevalence of CH increases as an individual ages and conveys a risk for progression to a malignancy. CH is thought to be driven by the underlying hematopoietic stem cells of an unknown quantity, with estimates in the literature for stem cell numbers differing by orders of magnitude. Previously, we developed a method using fluctuating CpG (fCpG) sites to serve as a fluctuating methylation clock to uncover stem cell dynamics in glandular tissues and orthogonally validated our method using publicly available datasets of human blood from normal cohorts and malignant cohorts. Here we expand on this work by presenting 38 new patients with distinct VAF groups from 1-2% VAF up to greater than 10% VAF for putative drivers with corresponding DNA methylation profiles using the Illumina EPIC array platform. We identify fCpG from our normal and CHIP cohorts to train and validate a machine learning approach that allows us to diagnose CHIP without DNA sequencing. Importantly, our approach allows for the identification of patients who may have CH driven by structural variants such as copy number alterations. We use this method to evaluate two publicly available methylation datasets of reportedly normal patients (n=656 and n=732) showing that evidence of CHIP can be found in 19% and 29% of these datasets, respectively. We then evaluate copy number differences in burden within our CHIP cohort and these newly identified CHIP cohorts. Using a mechanistic model of hematopoietic stem cells containing fCpGs we examine the temporal dynamics of competing founder CHIP drivers and the number of stem cells in the hematopoietic stem cell compartment. Citation Format: Ryan O. Schenck, Niels Asger Jakobsen, Virginia Turati, Darryl Shibata, Paresh Vyas, Simon Leedham, Alexander R.A. Anderson. Mutation agnostic diagnosis of clonal hematopoiesis of indeterminate potential (CHIP) using fluctuating methylation clocks [abstract]. In: Proceedings of the AACR Special Conference on the Evolutionary Dynamics in Carcinogenesis and Response to Therapy; 2022 Mar 14-17. Philadelphia (PA): AACR; Cancer Res 2022;82(10 Suppl):Abstract nr A019.

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Marnell, Christopher S., Alexander Bick, and Pradeep Natarajan. "Clonal hematopoiesis of indeterminate potential (CHIP): Linking somatic mutations, hematopoiesis, chronic inflammation and cardiovascular disease." Journal of Molecular and Cellular Cardiology 161 (December 2021): 98–105. http://dx.doi.org/10.1016/j.yjmcc.2021.07.004.

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Babushok, Daria V. "A brief, but comprehensive, guide to clonal evolution in aplastic anemia." Hematology 2018, no. 1 (November 30, 2018): 457–66. http://dx.doi.org/10.1182/asheducation-2018.1.457.

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Abstract Acquired aplastic anemia (AA) is an immune-mediated bone marrow aplasia that is strongly associated with clonal hematopoiesis upon marrow recovery. More than 70% of AA patients develop somatic mutations in their hematopoietic cells. In contrast to other conditions linked to clonal hematopoiesis, such as myelodysplastic syndrome (MDS) or clonal hematopoiesis of indeterminate potential in the elderly, the top alterations in AA are closely related to its immune pathogenesis. Nearly 40% of AA patients carry somatic mutations in the PIGA gene manifested as clonal populations of cells with the paroxysmal nocturnal hemoglobinuria phenotype, and 17% of AA patients have loss of HLA class I alleles. It is estimated that between 20% and 35% of AA patients have somatic mutations associated with hematologic malignancies, most characteristically in the ASXL1, BCOR, and BCORL1 genes. Risk factors for evolution to MDS in AA include the duration of disease, acquisition of high-risk somatic mutations, and age at AA onset. Emerging data suggest that several HLA class I alleles not only predispose to the development of AA but may also predispose to clonal evolution in AA patients. Long-term prospective studies are needed to determine the true prognostic implications of clonal hematopoiesis in AA. This article provides a brief, but comprehensive, review of our current understanding of clonal evolution in AA and concludes with 3 cases that illustrate a practical approach for integrating results of next-generation molecular studies into the clinical care of AA patients in 2018.

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DeZern, Amy E., Luca Malcovati, and Benjamin L. Ebert. "CHIP, CCUS, and Other Acronyms: Definition, Implications, and Impact on Practice." American Society of Clinical Oncology Educational Book, no. 39 (May 2019): 400–410. http://dx.doi.org/10.1200/edbk_239083.

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Unexplained blood cytopenias can be a clinical challenge for patients and clinicians alike. The relationship between these cytopenias and myeloid neoplasms like myelodysplastic syndromes (MDS) is currently an area of active research. There have been marked developments in our understanding of clonal hematopoiesis based on findings of somatic mutations in genes known to be associated with MDS. This has led to newer terms to describe precursor states to MDS, such as clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). These conditions may allow earlier diagnosis, modify surveillance for MDS, and guide additional therapies. This review summarizes recent updates in the field for affected patients.

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Godfrey, Sarah, Hannah Rosenblum, Jianhua Zhao, Megan Hawley, Harpreet Gill, Robert Daber, Sam Harris, et al. "CLONAL HEMATOPOIESIS OF INDETERMINATE POTENTIAL (CHIP) IN WILD-TYPE TRANSTHYRETIN CARDIAC AMYLOIDOSIS." Journal of the American College of Cardiology 77, no. 18 (May 2021): 3305. http://dx.doi.org/10.1016/s0735-1097(21)04659-3.

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Hirano, Teruyuki, and Scott E. Kasner. "Stranger Than Fiction, Clonal Hematopoiesis of Indeterminate Potential, and Small Vessel Pathology." Stroke 53, no. 3 (March 2022): 798–99. http://dx.doi.org/10.1161/strokeaha.121.037678.

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Burns, Sarah S., and Reuben Kapur. "Putative Mechanisms Underlying Cardiovascular Disease Associated with Clonal Hematopoiesis of Indeterminate Potential." Stem Cell Reports 15, no. 2 (August 2020): 292–306. http://dx.doi.org/10.1016/j.stemcr.2020.06.021.

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Journal articles on the topic 'Clonal hematopoiesis of indeterminate potential'

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