Clonal hematopoiesis is associated with risk of severe Covid-19

AbstractAcquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival. These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH. A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19. Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 525 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we show that CH is associated with severe Covid-19 outcomes (OR = 1.85, 95%=1.15–2.99, p = 0.01), in particular CH characterized by non-cancer driver mutations (OR = 2.01, 95% CI = 1.15–3.50, p = 0.01). We further explore the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH is significantly associated with risk of Clostridium Difficile (HR = 2.01, 95% CI: 1.22–3.30, p = 6×10−3) and Streptococcus/Enterococcus infections (HR = 1.56, 95% CI = 1.15–2.13, p = 5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

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Clonal hematopoiesis is associated with risk of severe Covid-19

10.1101/2020.11.25.20233163 ◽

2020 ◽

Author(s):

Kelly L. Bolton ◽

Youngil Koh ◽

Michael B. Foote ◽

Hogune Im ◽

Justin Jee ◽

...

Keyword(s):

Somatic Mutations ◽

Malignant Diseases ◽

Tumor Patients ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Stem And Progenitor Cells ◽

Severe Infections ◽

The Relationship ◽

Immunologic Profile

ABSTRACTAcquired somatic mutations in hematopoietic stem and progenitor cells (clonal hematopoiesis or CH) are associated with advanced age, increased risk of cardiovascular and malignant diseases, and decreased overall survival.1–4 These adverse sequelae may be mediated by altered inflammatory profiles observed in patients with CH.2,5,6 A pro-inflammatory immunologic profile is also associated with worse outcomes of certain infections, including SARS-CoV-2 and its associated disease Covid-19.7,8 Whether CH predisposes to severe Covid-19 or other infections is unknown. Among 515 individuals with Covid-19 from Memorial Sloan Kettering (MSK) and the Korean Clonal Hematopoiesis (KoCH) consortia, we found that CH was associated with severe Covid-19 outcomes (OR=1.9, 95%=1.2-2.9, p=0.01). We further explored the relationship between CH and risk of other infections in 14,211 solid tumor patients at MSK. CH was significantly associated with risk of Clostridium Difficile (HR=2.0, 95% CI: 1.2-3.3, p=6×10−3) and Streptococcus/Enterococcus infections (HR=1.5, 95% CI=1.1-2.1, p=5×10−3). These findings suggest a relationship between CH and risk of severe infections that warrants further investigation.

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Aging, hematopoiesis, and the myelodysplastic syndromes

Blood Advances ◽

10.1182/bloodadvances.2017009852 ◽

2017 ◽

Vol 1 (26) ◽

pp. 2572-2578 ◽

Cited By ~ 12

Author(s):

Stephen S. Chung ◽

Christopher Y. Park

Keyword(s):

Myelodysplastic Syndromes ◽

Bone Marrow Failure ◽

Hematologic Malignancies ◽

Relative Increase ◽

Extrinsic Factors ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

The Many ◽

The Relationship

Abstract The aging hematopoietic system undergoes numerous changes, including reduced production of red blood cells and lymphocytes as well as a relative increase in the production of myeloid cells. Emerging evidence indicates that many of these changes are due to selection pressures from cell-intrinsic and cell-extrinsic factors that result in clonal shifts in the hematopoietic stem cell (HSC) pool, resulting in predominant HSC clones that exhibit the functional characteristics associated with HSC aging. Given the recent descriptions of clonal hematopoiesis in aged populations, the increased risk of developing hematologic malignancies in individuals with clonal hematopoiesis, and the many similarities in hematopoietic aging and acquired bone marrow failure (BMF) syndromes, such as myelodysplastic syndromes (MDS), this raises significant questions regarding the relationship between aging hematopoiesis and MDS, including the factors that regulate HSC aging, whether clonal hematopoiesis is required for the development of MDS, and even whether BMF is an inevitable consequence of aging. In this article, we will review our current understanding of these processes and the potential intersections among them.

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Aging, hematopoiesis, and the myelodysplastic syndromes

Hematology ◽

10.1182/asheducation-2017.1.73 ◽

2017 ◽

Vol 2017 (1) ◽

pp. 73-78 ◽

Cited By ~ 6

Author(s):

Stephen S. Chung ◽

Christopher Y. Park

Keyword(s):

Myelodysplastic Syndromes ◽

Bone Marrow Failure ◽

Hematologic Malignancies ◽

Relative Increase ◽

Extrinsic Factors ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

The Many ◽

The Relationship

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Increased prevalence of clonal hematopoiesis of indeterminate potential amongst people living with HIV

Scientific Reports ◽

10.1038/s41598-021-04308-2 ◽

2022 ◽

Vol 12 (1) ◽

Author(s):

Alexander G. Bick ◽

Konstantin Popadin ◽

Christian W. Thorball ◽

Md Mesbah Uddin ◽

Markella V. Zanni ◽

...

Keyword(s):

Hematologic Malignancy ◽

Driver Mutations ◽

People Living With Hiv ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Age Related ◽

Increased Risk ◽

Study Population ◽

Artery Disease ◽

Living With Hiv

AbstractPeople living with human immunodeficiency virus (PLWH) have significantly increased risk for cardiovascular disease in part due to inflammation and immune dysregulation. Clonal hematopoiesis of indeterminate potential (CHIP), the age-related acquisition and expansion of hematopoietic stem cells due to leukemogenic driver mutations, increases risk for both hematologic malignancy and coronary artery disease (CAD). Since increased inflammation is hypothesized to be both a cause and consequence of CHIP, we hypothesized that PLWH have a greater prevalence of CHIP. We searched for CHIP in multi-ethnic cases from the Swiss HIV Cohort Study (SHCS, n = 600) and controls from the Atherosclerosis Risk in the Communities study (ARIC, n = 8111) from blood DNA-derived exome sequences. We observed that HIV is associated with a twofold increase in CHIP prevalence, both in the whole study population and in a subset of 230 cases and 1002 matched controls selected by propensity matching to control for demographic imbalances (SHCS 7%, ARIC 3%, p = 0.005). We also observed that ASXL1 is the most commonly mutated CHIP-associated gene in PLWH. Our results suggest that CHIP may contribute to the excess cardiovascular risk observed in PLWH.

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Myelopoiesis during Solid Cancers and Strategies for Immunotherapy

Cells ◽

10.3390/cells10050968 ◽

2021 ◽

Vol 10 (5) ◽

pp. 968

Author(s):

Tyler J. Wildes ◽

Bayli DiVita Dean ◽

Catherine T. Flores

Keyword(s):

Myeloid Cells ◽

Hematopoietic Stem ◽

Cell Therapies ◽

Broad Array ◽

Stem And Progenitor Cells ◽

Recent Developments ◽

Immature Myeloid Cells ◽

Significant Discovery ◽

The Relationship ◽

Clinical Advances

Our understanding of the relationship between the immune system and cancers has undergone significant discovery recently. Immunotherapy with T cell therapies and checkpoint blockade has meaningfully changed the oncology landscape. While remarkable clinical advances in adaptive immunity are occurring, modulation of innate immunity has proven more difficult. The myeloid compartment, including macrophages, neutrophils, and dendritic cells, has a significant impact on the persistence or elimination of tumors. Myeloid cells, specifically in the tumor microenvironment, have direct contact with tumor tissue and coordinate with tumor-reactive T cells to either stimulate or antagonize cancer immunity. However, the myeloid compartment comprises a broad array of cells in various stages of development. In addition, hematopoietic stem and progenitor cells at various stages of myelopoiesis in distant sites undergo significant modulation by tumors. Understanding how tumors exert their influence on myeloid progenitors is critical to making clinically meaningful improvements in these pathways. Therefore, this review will cover recent developments in our understanding of how solid tumors modulate myelopoiesis to promote the formation of pro-tumor immature myeloid cells. Then, it will cover some of the potential avenues for capitalizing on these mechanisms to generate antitumor immunity.

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Myelodysplastic Syndromes in the Postgenomic Era and Future Perspectives for Precision Medicine

Cancers ◽

10.3390/cancers13133296 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3296

Author(s):

Ioannis Chanias ◽

Kristina Stojkov ◽

Gregor Stehle ◽

Michael Daskalakis ◽

Helena Simeunovic ◽

...

Keyword(s):

Precision Medicine ◽

Myelodysplastic Syndromes ◽

Clonal Evolution ◽

Driver Mutations ◽

Future Perspectives ◽

Hematopoietic Stem ◽

Secondary Acute Myeloid Leukemia ◽

Stem And Progenitor Cells ◽

Unfit Patients ◽

Generation Sequencing

Myelodysplastic syndromes (MDS) represent a heterogeneous group of clonal disorders caused by sequential accumulation of somatic driver mutations in hematopoietic stem and progenitor cells (HSPCs). MDS is characterized by ineffective hematopoiesis with cytopenia, dysplasia, inflammation, and a variable risk of transformation into secondary acute myeloid leukemia. The advent of next-generation sequencing has revolutionized our understanding of the genetic basis of the disease. Nevertheless, the biology of clonal evolution remains poorly understood, and the stochastic genetic drift with sequential accumulation of genetic hits in HSPCs is individual, highly dynamic and hardly predictable. These continuously moving genetic targets pose substantial challenges for the implementation of precision medicine, which aims to maximize efficacy with minimal toxicity of treatments. In the current postgenomic era, allogeneic hematopoietic stem cell transplantation remains the only curative option for younger and fit MDS patients. For all unfit patients, regeneration of HSPCs stays out of reach and all available therapies remain palliative, which will eventually lead to refractoriness and progression. In this review, we summarize the recent advances in our understanding of MDS pathophysiology and its impact on diagnosis, risk-assessment and disease monitoring. Moreover, we present ongoing clinical trials with targeting compounds and highlight future perspectives for precision medicine.

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The Genetics of Myelodysplastic Syndromes: Clinical Relevance

Genes ◽

10.3390/genes12081144 ◽

2021 ◽

Vol 12 (8) ◽

pp. 1144

Author(s):

Chiara Chiereghin ◽

Erica Travaglino ◽

Matteo Zampini ◽

Elena Saba ◽

Claudia Saitta ◽

...

Keyword(s):

Disease Progression ◽

Myelodysplastic Syndromes ◽

Clinical Relevance ◽

Driver Mutations ◽

Significant Information ◽

Hematopoietic Stem ◽

Probability Of Survival ◽

Mutational Status ◽

Increased Risk ◽

Risk Of Disease

Myelodysplastic syndromes (MDS) are a clonal disease arising from hematopoietic stem cells, that are characterized by ineffective hematopoiesis (leading to peripheral blood cytopenia) and by an increased risk of evolution into acute myeloid leukemia. MDS are driven by a complex combination of genetic mutations that results in heterogeneous clinical phenotype and outcome. Genetic studies have enabled the identification of a set of recurrently mutated genes which are central to the pathogenesis of MDS and can be organized into a limited number of cellular pathways, including RNA splicing (SF3B1, SRSF2, ZRSR2, U2AF1 genes), DNA methylation (TET2, DNMT3A, IDH1/2), transcription regulation (RUNX1), signal transduction (CBL, RAS), DNA repair (TP53), chromatin modification (ASXL1, EZH2), and cohesin complex (STAG2). Few genes are consistently mutated in >10% of patients, whereas a long tail of 40–50 genes are mutated in <5% of cases. At diagnosis, the majority of MDS patients have 2–4 driver mutations and hundreds of background mutations. Reliable genotype/phenotype relationships were described in MDS: SF3B1 mutations are associated with the presence of ring sideroblasts and more recent studies indicate that other splicing mutations (SRSF2, U2AF1) may identify distinct disease categories with specific hematological features. Moreover, gene mutations have been shown to influence the probability of survival and risk of disease progression and mutational status may add significant information to currently available prognostic tools. For instance, SF3B1 mutations are predictors of favourable prognosis, while driver mutations of other genes (such as ASXL1, SRSF2, RUNX1, TP53) are associated with a reduced probability of survival and increased risk of disease progression. In this article, we review the most recent advances in our understanding of the genetic basis of myelodysplastic syndromes and discuss its clinical relevance.

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Secondary CNL after SAA reveals insights in leukemic transformation of bone marrow failure syndromes

Blood Advances ◽

10.1182/bloodadvances.2020001541 ◽

2020 ◽

Vol 4 (21) ◽

pp. 5540-5546

Author(s):

Laurent Schmied ◽

Patricia A. Olofsen ◽

Pontus Lundberg ◽

Alexandar Tzankov ◽

Martina Kleber ◽

...

Keyword(s):

Bone Marrow ◽

Aplastic Anemia ◽

Myeloid Leukemia ◽

Bone Marrow Failure ◽

Driver Mutations ◽

Leukemic Transformation ◽

Hematopoietic Stem ◽

Bone Marrow Failure Syndromes ◽

Proinflammatory Responses ◽

Stem And Progenitor Cells

Abstract Acquired aplastic anemia and severe congenital neutropenia (SCN) are bone marrow (BM) failure syndromes of different origin, however, they share a common risk for secondary leukemic transformation. Here, we present a patient with severe aplastic anemia (SAA) evolving to secondary chronic neutrophilic leukemia (CNL; SAA-CNL). We show that SAA-CNL shares multiple somatic driver mutations in CSF3R, RUNX1, and EZH2/SUZ12 with cases of SCN that transformed to myelodysplastic syndrome or acute myeloid leukemia (AML). This molecular connection between SAA-CNL and SCN progressing to AML (SCN-AML) prompted us to perform a comparative transcriptome analysis on nonleukemic CD34high hematopoietic stem and progenitor cells, which showed transcriptional profiles that resemble indicative of interferon-driven proinflammatory responses. These findings provide further insights in the mechanisms underlying leukemic transformation in BM failure syndromes.

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Clonal hematopoiesis in donors and long-term survivors of related allogeneic hematopoietic stem cell transplantation

Blood ◽

10.1182/blood.2019003079 ◽

2020 ◽

Vol 135 (18) ◽

pp. 1548-1559 ◽

Cited By ~ 8

Author(s):

Steffen Boettcher ◽

C. Matthias Wilk ◽

Jochen Singer ◽

Fabian Beier ◽

Elodie Burcklen ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplantation ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Long Term Survivors

Abstract Clonal hematopoiesis (CH) is associated with age and an increased risk of myeloid malignancies, cardiovascular risk, and all-cause mortality. We tested for CH in a setting where hematopoietic stem cells (HSCs) of the same individual are exposed to different degrees of proliferative stress and environments, ie, in long-term survivors of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and their respective related donors (n = 42 donor-recipient pairs). With a median follow-up time since allo-HSCT of 16 years (range, 10-32 years), we found a total of 35 mutations in 23 out of 84 (27.4%) study participants. Ten out of 42 donors (23.8%) and 13 out of 42 recipients (31%) had CH. CH was associated with older donor and recipient age. We identified 5 cases of donor-engrafted CH, with 1 case progressing into myelodysplastic syndrome in both donor and recipient. Four out of 5 cases showed increased clone size in recipients compared with donors. We further characterized the hematopoietic system in individuals with CH as follows: (1) CH was consistently present in myeloid cells but varied in penetrance in B and T cells; (2) colony-forming units (CFUs) revealed clonal evolution or multiple independent clones in individuals with multiple CH mutations; and (3) telomere shortening determined in granulocytes suggested ∼20 years of added proliferative history of HSCs in recipients compared with their donors, with telomere length in CH vs non-CH CFUs showing varying patterns. This study provides insight into the long-term behavior of the same human HSCs and respective CH development under different proliferative conditions.

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HLA Class I Allele-Lacking Hematopoietic Stem/Progenitor Cells Support Long-Term Clonal Hematopoiesis without Oncogenic Driver Mutations in Acquired Aplastic Anemia

Blood ◽

10.1182/blood.v128.22.3894.3894 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3894-3894

Author(s):

Tatsuya Imi ◽

Takamasa Katagiri ◽

Kazuyoshi Hosomichi ◽

Noriharu Nakagawa ◽

Yoshitaka Zaimoku ◽

...

Keyword(s):

Aplastic Anemia ◽

Progenitor Cells ◽

Somatic Mutations ◽

Hla Class I ◽

Driver Mutations ◽

Hematopoietic Stem ◽

Target Sequencing ◽

Clonal Hematopoiesis ◽

Oncogenic Driver

Abstract [Background] Clonal hematopoiesis is currently known to be common in patients with acquired aplastic anemia (AA). One of the most common abnormalities underlying clonal hematopoiesis in AA patients is copy-number neutral loss of heterozygosity (LOH) in the short of 6 chromosome (6pLOH) caused by acquired uniparental disomy. Hematopoietic stem/progenitor cells (HSPCs) having undergone 6pLOH are thought to evade attack by cytotoxic T lymphocytes (CTLs) specific to auto-antigens by lacking particular HLA-A alleles. These HSPCs then produce HLA class I allele-lacking [HLA(-)] leukocytes to support hematopoiesis in patients with AA patients in remission. Our recent study showed that HLA(-) granulocytes are detected in about 24% of newly-diagnosed AA patients, and the aberrant granulocytes often account for more than 95% of the total granulocytes and persist for many years. The sustainability of 6pLOH(+) HSPC clones suggests that these HSPCs may suffer from secondary somatic mutations that confer a proliferative advantage on them over normal HSPCs. Alternatively, 6pLOH(+) HSPCs may persist and continue to support hematopoiesis according to their inherent sustainability, just like the PIGA mutant HSPCs we previously described (Katagiri et al. Stem Cells, 2013). To test these hypotheses, we determined the sequences of genes associated with the clonal expansion of HSPCs in HLA(-) granulocytes. [Patients and Methods] Eleven AA patients whose percentages of HLA(-) granulocytes ranged 6.4%-99.8% (median 94.2%) of the total granulocyte population were chosen for this study. The patients (male/female, 5/6 and age 27-79 [median 53] years) had been diagnosed with severe (n=5) or non-severe (n=6) AA 2-25 [median 12.5] years earlier, and 7 and 4 patients achieved complete response and partial response, respectively after treatments with cyclosporine (CsA) alone (n=4), CsA+antithymocyte globulin (ATG, n=3), CsA+anabolic steroids (AS, n=2), AS+romiplostim (n=1), and AS alone (n=1). The lineage combinations of HLA(-) cells were granulocyte, monocytes, B cells and T cells (GMBT) in 6, GMB in 4 and GM in 1. HLA(-) and normal [HLA(+)] granulocytes were sorted from the blood leukocytes of the 11 patients and the DNA of each cell population as well as that of buccal mucosa cells was subjected to target sequencing of 61 myelodysplastic syndrome (MDS)-related genes with MiSeq. DNA samples from 5 patients including 4 patients whose HLA(-) cell percentages were greater than 95% were further analyzed by whole-exome sequencing (WES) using HiSeq. The percentage of 6pLOH(+) cells in the total granulocytes or sorted HLA(-) granulocytes were estimated using digital droplet PCR or deep sequencing of HLA alleles. [Results] Target sequencing of 8 of the 11 patients revealed somatic mutations in the HLA(-) granulocytes of 3 patients. HLA(-) granulocytes-specific mutations were found in DNMT3A, PRR5L, SMC3A, and LRCH1 (Table). The variant allele frequencies (VAF) of these mutations were far lower (5.1%-20%) than those of HLA(-) granulocytes that accounted for 95% of sorted cells. WES revealed 22 non-synonymous and 9 synonymous mutations in the HLA(-) granulocytes from 4 of the 5 patientsthat included 3 new patients and 2 patients whose samples were negative for mutations revealed by the target sequencing. The VAF of these mutations ranged from 20.7-52.5% (median 44.1%, Table). Very-high VAFs of several mutant genes suggested that these mutations occurred simultaneously with or soon after the occurrence of 6pLOH. A patient who achieved remission after romiplostim therapy without ATG showed various gene mutations that were thought to have occurred after 6pLOH. Despite of their highly biased hematopoiesis supported by single or few clones, recurrent or MDS-related oncogenic mutations were not detected in any of the 11 patients. Of note, the percentages of 6pLOH(+) cells in the sorted HLA(-) granulocytes were ≤75% (36.7%, 46%, 74%, and 75%) in 4 patients, indicating the presence of granulocytes lacking HLA-A alleles through mechanisms other than 6pLOH. [Conclusions] HLA(-) HSPCs caused by 6pLOH or other unknown mechanisms support long-term hematopoiesis without the development of oncogenic driver mutations that are associated with clonal hematopoiesis of MDS; as such, clonal hematopoiesis by 6pLOH(+) HSPCs may not portend a poor prognosis. Disclosures Nakao: Alexion Pharmaceuticals: Honoraria, Research Funding.

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