Aging, hematopoiesis, and the myelodysplastic syndromes

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

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

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Clonal hematopoiesis is associated with risk of severe Covid-19

Nature Communications ◽

10.1038/s41467-021-26138-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Kelly L. Bolton ◽

Youngil Koh ◽

Michael B. Foote ◽

Hogune Im ◽

Justin Jee ◽

...

Keyword(s):

Driver Mutations ◽

Tumor Patients ◽

Hematopoietic Stem ◽

Cancer Driver ◽

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. 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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Risk and timing of cardiovascular death among patients with myelodysplastic syndromes

Blood Advances ◽

10.1182/bloodadvances.2017010165 ◽

2017 ◽

Vol 1 (23) ◽

pp. 2032-2040 ◽

Cited By ~ 26

Author(s):

Andrew M. Brunner ◽

Traci M. Blonquist ◽

Gabriela S. Hobbs ◽

Philip C. Amrein ◽

Donna S. Neuberg ◽

...

Keyword(s):

General Population ◽

Myelodysplastic Syndromes ◽

Lower Risk ◽

Clinical Care ◽

Cardiovascular Death ◽

Standardized Mortality Ratio ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Mortality Ratio

Abstract Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders associated with progression to leukemia and poor survival. Clonal hematopoiesis in people without an MDS diagnosis carries an increased risk of cardiovascular death. Many clonally restricted mutations are shared between patients with MDS and those with non-MDS clonal hematopoiesis; therefore, we evaluated the risk of cardiovascular death among patients with MDS. We evaluated adults with MDS in the Surveillance, Epidemiology, and End Results database of the National Cancer Institute and compared them with the general population living in the same states. We grouped histological subtypes of MDS into lower-, intermediate-, and higher-risk disease. The primary outcomes were overall survival and primary cause of death (COD) as reported to state registries. A total of 21 372 patients with MDS between 2001 and 2011 died during follow-up with a known COD. The rate of death due to cardiovascular disease (CVD) was 4613 per 100 000 person-years, compared with 2091 in the age- and-sex-adjusted US population (standardized mortality ratio, 2.21). At 24 months, the cumulative incidence of death attributed to MDS or leukemia was 23% vs 8% for CVD. Among those alive at 60 months, 27% eventually died of CVD compared with 29% from MDS or leukemia; those with lower-risk disease who survived >60 months had more deaths attributed to cardiovascular causes (30%; 95% confidence interval [CI], 26.7-33.2%) than MDS itself (24%; 95% CI, 21.4-27.5%). Patients with MDS are more likely to die of cardiovascular causes than the general population. Modifying cardiovascular risk factors, especially among those with lower-risk disease, may be warranted for MDS-related clinical care.

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Safety and efficacy of azacitidine in elderly patients with intermediate to high-risk myelodysplastic syndromes

Therapeutic Advances in Hematology ◽

10.1177/2040620716674677 ◽

2016 ◽

Vol 8 (1) ◽

pp. 21-27 ◽

Cited By ~ 6

Author(s):

Shyamala C. Navada ◽

Lewis R. Silverman

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Older Patients ◽

Bone Marrow Failure ◽

Common Adverse Effect ◽

The United States ◽

International Prognostic Scoring System ◽

Hematopoietic Stem ◽

Risk Of Death ◽

Increased Risk

Myelodysplastic syndromes (MDS) represent a clonal hematopoietic stem cell disorder characterized by morphologic features of dyspoiesis, a hyperproliferative bone marrow, and one or more peripheral blood cytopenias. In patients classified according to the Revised International Prognostic Scoring System (R-IPSS) with intermediate or higher-risk disease, there is an increased risk of death due to progressive bone marrow failure or transformation to acute myeloid leukemia (AML). Azacitidine was the first DNA hypomethylating agent approved by the United States (US) Food and Drug Administration (FDA) for the treatment of MDS and the only therapy that has demonstrated a significant survival benefit over conventional care regimens (CCRs) in patients with intermediate or higher-risk disease. Prolonged survival is independent of achieving a complete remission. Azacitidine has been used in older patients with both clinical and hematological improvement as well as an acceptable side effect profile. The most common adverse effect is myelosuppression. These findings support the use of azacitidine as an effective treatment in older patients with higher-risk MDS.

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Hematopoietic Stem and Progenitor Cell Aging is Initiated at Middle Age Through Decline in Local Insulin-Like Growth Factor 1 (IGF1)

10.1101/2020.07.11.198846 ◽

2020 ◽

Author(s):

Kira Young ◽

Elizabeth Eudy ◽

Rebecca Bell ◽

Matthew Loberg ◽

Tim Stearns ◽

...

Keyword(s):

Progenitor Cell ◽

Middle Age ◽

Functional Decline ◽

Hematologic Malignancies ◽

Cell Aging ◽

Direct Stimulation ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Vaccination Response ◽

Increased Risk

AbstractHematopoietic stem cells (HSCs) are responsible for lifelong maintenance and regeneration of the blood system. With aging, loss of HSC function is a major contributor to decline in overall hematopoietic function, leading to increased rate of infection, poor vaccination response, clonal hematopoiesis, and increased risk of hematologic malignancies. While cellular and molecular hallmarks of HSC aging have been defined1–3, the lack of understanding of the nature and timing of the initiating events that cause HSC aging is a barrier to achieving the goal of extending healthy hematopoietic function into older age. Here we discover that hallmarks of HSC aging and myeloid-biased hematopoiesis accumulate by middle age in mice, and that the bone marrow (BM) microenvironment at middle age induces and is indispensable for hematopoietic aging phenotypes. Using unbiased transcriptome-based approaches, we identify decreased production of IGF1 by cells in the middle-aged BM microenvironment as a factor causing hematopoietic stem and progenitor cell aging and show that direct stimulation with IGF1 rescues hallmarks of hematopoietic aging. Declining IGF1 in the BM microenvironment at middle age represents a compelling target for intervention using prophylactic therapies to effectively extend healthspan and to prevent functional decline during aging.

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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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How I treat myelodysplastic syndromes of childhood

Blood ◽

10.1182/blood-2017-09-765214 ◽

2018 ◽

Vol 131 (13) ◽

pp. 1406-1414 ◽

Cited By ~ 19

Author(s):

Franco Locatelli ◽

Brigitte Strahm

Keyword(s):

Bone Marrow ◽

Myelodysplastic Syndromes ◽

Germ Line ◽

Bone Marrow Failure ◽

Hematologic Malignancies ◽

Suppressive Therapy ◽

Severe Neutropenia ◽

Complex Karyotype ◽

Hematopoietic Stem ◽

Monosomy 7

Abstract Pediatric myelodysplastic syndromes (MDSs) are a heterogeneous group of clonal disorders with an annual incidence of 1 to 4 cases per million, accounting for less than 5% of childhood hematologic malignancies. MDSs in children often occur in the context of inherited bone marrow failure syndromes, which represent a peculiarity of myelodysplasia diagnosed in pediatric patients. Moreover, germ line syndromes predisposing individuals to develop MDS or acute myeloid leukemia have recently been identified, such as those caused by mutations in GATA2, ETV6, SRP72, and SAMD9/SAMD9-L. Refractory cytopenia of childhood (RCC) is the most frequent pediatric MDS variant, and it has specific histopathologic features. Allogeneic hematopoietic stem cell transplantation (HSCT) is the treatment of choice for many children with MDSs and is routinely offered to all patients with MDS with excess of blasts, to those with MDS secondary to previously administered chemoradiotherapy, and to those with RCC associated with monosomy 7, complex karyotype, severe neutropenia, or transfusion dependence. Immune-suppressive therapy may be a treatment option for RCC patients with hypocellular bone marrow and the absence of monosomy 7 or a complex karyotype, although the response rate is lower than that observed in severe aplastic anemia, and a relevant proportion of these patients will subsequently need HSCT for either nonresponse or relapse.

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CHIP: is clonal hematopoiesis a surrogate for aging and other disease?

Hematology ◽

10.1182/hematology.2021000270 ◽

2021 ◽

Vol 2021 (1) ◽

pp. 384-389

Author(s):

Lukasz P. Gondek

Keyword(s):

Tumor Suppressors ◽

Somatic Mutations ◽

Hematologic Malignancies ◽

Environmental Stressors ◽

Hematopoietic Tissue ◽

Compensatory Mechanisms ◽

Hematopoietic Stem ◽

Clonal Hematopoiesis ◽

Increased Risk ◽

Immune Attack

Abstract Somatic mutations are an unavoidable consequence of aging tissues. Even though most mutations are functionally silent, some may affect genes critical to proper tissue self-renewal and differentiation, resulting in the outgrowth of affected cells, also known as clonal expansion. In hematopoietic tissue such clonal dominance is known as clonal hematopoiesis (CH). Sporadic CH is frequent in aging and affects over 10% of individuals beyond the fifth decade of life. It has been associated with an increased risk of hematologic malignancies and cardiovascular disease. In addition to aging, CH has been observed in other hematologic conditions and confers an adaptation of hematopoietic stem cells (HSCs) to various environmental stressors and cell-intrinsic defects. In the presence of extrinsic stressors such as genotoxic therapies, T-cell-mediated immune attack, or inflammation, somatic mutations may result in augmentation of HSC fitness. Such attuned HSCs can evade the environmental insults and outcompete their unadapted counterparts. Similarly, in inherited bone marrow failures, somatic mutations in HSCs frequently lead to the reversion of inherited defects. This may occur via the direct correction of germline mutations or indirect compensatory mechanisms. Occasionally, such adaptation may involve oncogenes or tumor suppressors, resulting in malignant transformation. In this brief article, we focus on the mechanisms of clonal dominance in various clinical and biological contexts.

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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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Paroxysmal Nocturnal Hemoglobinuria Clones Are Infrequent in Hepatitis-Associated Aplastic Anemia at the Time of Diagnosis

Blood ◽

10.1182/blood-2019-125620 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5016-5016

Author(s):

Wenrui Yang ◽

Xin Zhao ◽

Guangxin Peng ◽

Li Zhang ◽

Liping Jing ◽

...

Keyword(s):

Aplastic Anemia ◽

Paroxysmal Nocturnal Hemoglobinuria ◽

Conflicts Of Interest ◽

Bone Marrow Failure ◽

Clonal Evolution ◽

Extrinsic Factors ◽

Clone Size ◽

Hematopoietic Stem ◽

Over Time ◽

Pnh Clone

Aplastic anemia (AA) is an immune-mediated bone marrow failure, resulting in reduced number of hematopoietic stem and progenitor cells and pancytopenia. The presence of paroxysmal nocturnal hemoglobinuria (PNH) clone in AA usually suggests an immunopathogenesis in patients. However, when and how PNH clone emerge in AA is still unclear. Hepatitis associated aplastic anemia (HAAA) is a special variant of AA with a clear disease course and relatively explicit immune pathogenesis, thus serves as a good model to explore the emergence and expansion of PNH clone. To evaluate the frequency and clonal evolution of PNH clones in AA, we retrospectively analyzed the clinical data of 90 HAAA patients that were consecutively diagnosed between August 2006 and March 2018 in Blood Diseases Hospital, and we included 403 idiopathic AA (IAA) patients as control. PNH clones were detected in 8 HAAA patients (8.9%,8/90) at the time of diagnosis, compared to 18.1% (73/403) in IAA. Eight HAAA patients had PNH clone in granulocytes with a median clone size of 3.90% (1.09-12.33%), and 3 patients had PNH clone in erythrocytes (median 4.29%, range 2.99-10.8%). Only one HAAA patients (1/8, 12.5%) had a PNH clone larger than 10%, while 24 out of 73 IAA patients (32.9%) had larger PNH clones. Taken together, we observed a less frequent PNH clone with smaller clone size in HAAA patients, compared to that in IAAs. We next attempted to find out factors that associated with PNH clones. We first split patients with HAAA into two groups based on the length of disease history (≥3 mo and < 3mo). There were more patients carried PNH clone in HAAA with longer history (21.4%, 3/14) than patients with shorter history (6.6%, 5/76), in line with higher incidence of PNH clone in IAA patients who had longer disease history. Then we compared the PNH clone incidence between HAAA patients with higher absolute neutrophil counts (ANC, ≥0.2*109/L) and lower ANC (< 0.2*109/L). Interestingly, very few VSAA patients developed PNH clone (5%, 3/60), while 16.7% (5/30) of non-VSAA patients had PNH clone at diagnosis. We monitored the evolution of PNH clones after immunosuppressive therapy, and found increased incidence of PNH clone over time. The overall frequency of PNH clone in HAAA was 20.8% (15/72), which was comparable to that in IAA (27.8%, 112/403). Two thirds of those new PNH clones occurred in non-responders in HAAA. In conclusion, PNH clones are infrequent in HAAA compared to IAA at the time of diagnosis, but the overall frequency over time are comparable between the two groups of patients. In SAA/VSAA patients who are under the activated abnormal immunity, longer clinical course and relatively adequate residual hematopoietic cells serve as two important extrinsic factors for HSCs with PIGA-mutation to escape from immune attack and to expand. Disclosures No relevant conflicts of interest to declare.

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