Publications by authors named "Christopher J Gibson"

48 Publications

Clonal hematopoiesis in patients receiving chimeric antigen receptor T-cell therapy.

Blood Adv 2021 08;5(15):2982-2986

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Chimeric antigen receptor (CAR) T-cells have emerged as an efficacious modality in patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM). Clonal hematopoiesis of indeterminate potential (CHIP), a state in which mutations in hematopoietic cells give rise to a clonal population of cells, is more common in patients exposed to cytotoxic therapies, has been shown to influence inflammatory immune programs, and is associated with an adverse prognosis in patients with NHL and MM receiving autologous transplantation. We therefore hypothesized that CHIP could influence clinical outcomes in patients receiving CAR T-cell therapy. In a cohort of 154 patients with NHL or MM receiving CAR T-cells, we found that CHIP was present in 48% of patients and associated with increased rates of complete response and cytokine release syndrome severity, but only in patients younger than age 60 years. Despite these differences, CHIP was not associated with a difference in progression-free or overall survival, regardless of age. Our data suggest that CHIP can influence CAR T-cell biology and clinical outcomes, but, in contrast to autologous transplantation, CHIP was not associated with worse survival and should not be a reason to exclude individuals from receiving this potentially life-prolonging treatment.
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http://dx.doi.org/10.1182/bloodadvances.2021004554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8361461PMC
August 2021

The clinical and functional effects of TERT variants in myelodysplastic syndrome.

Blood 2021 Sep;138(10):898-911

Division of Hematological Malignancies, Department of Medical Oncology, and.

Germline pathogenic TERT variants are associated with short telomeres and an increased risk of developing myelodysplastic syndrome (MDS) among patients with a telomere biology disorder. We identified TERT rare variants in 41 of 1514 MDS patients (2.7%) without a clinical diagnosis of a telomere biology disorder who underwent allogeneic transplantation. Patients with a TERT rare variant had shorter telomere length (P < .001) and younger age at MDS diagnosis (52 vs 59 years, P = .03) than patients without a TERT rare variant. In multivariable models, TERT rare variants were associated with inferior overall survival (P = .034) driven by an increased incidence of nonrelapse mortality (NRM; P = .015). Death from a noninfectious pulmonary cause was more frequent among patients with a TERT rare variant. Most variants were missense substitutions and classified as variants of unknown significance. Therefore, we cloned all rare missense variants and quantified their impact on telomere elongation in a cell-based assay. We found that 90% of TERT rare variants had severe or intermediate impairment in their capacity to elongate telomeres. Using a homology model of human TERT bound to the shelterin protein TPP1, we inferred that TERT rare variants disrupt domain-specific functions, including catalysis, protein-RNA interactions, and recruitment to telomeres. Our results indicate that the contribution of TERT rare variants to MDS pathogenesis and NRM risk is underrecognized. Routine screening for TERT rare variants in MDS patients regardless of age or clinical suspicion may identify clinically inapparent telomere biology disorders and improve transplant outcomes through risk-adapted approaches.
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http://dx.doi.org/10.1182/blood.2021011075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432045PMC
September 2021

Distinct genetic pathways define pre-malignant versus compensatory clonal hematopoiesis in Shwachman-Diamond syndrome.

Nat Commun 2021 02 26;12(1):1334. Epub 2021 Feb 26.

Dartmouth-Hitchcock Medical Center, Pediatric Hematology Oncology, Geisel School of Medicine, Lebanon, NH, USA.

To understand the mechanisms that mediate germline genetic leukemia predisposition, we studied the inherited ribosomopathy Shwachman-Diamond syndrome (SDS), a bone marrow failure disorder with high risk of myeloid malignancies at an early age. To define the mechanistic basis of clonal hematopoiesis in SDS, we investigate somatic mutations acquired by patients with SDS followed longitudinally. Here we report that multiple independent somatic hematopoietic clones arise early in life, most commonly harboring heterozygous mutations in EIF6 or TP53. We show that germline SBDS deficiency establishes a fitness constraint that drives selection of somatic clones via two distinct mechanisms with different clinical consequences. EIF6 inactivation mediates a compensatory pathway with limited leukemic potential by ameliorating the underlying SDS ribosome defect and enhancing clone fitness. TP53 mutations define a maladaptive pathway with enhanced leukemic potential by inactivating tumor suppressor checkpoints without correcting the ribosome defect. Subsequent development of leukemia was associated with acquisition of biallelic TP53 alterations. These results mechanistically link leukemia predisposition to germline genetic constraints on cellular fitness, and provide a rational framework for clinical surveillance strategies.
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http://dx.doi.org/10.1038/s41467-021-21588-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7910481PMC
February 2021

Short telomere length predicts nonrelapse mortality after stem cell transplantation for myelodysplastic syndrome.

Blood 2020 12;136(26):3070-3081

Division of Hematological Malignancies, Department of Medical Oncology, and.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative treatment for patients with myelodysplastic syndrome (MDS), but long-term survival is limited by the risk of transplant-related complications. Short telomere length, mediated by inherited or acquired factors, impairs cellular response to genotoxic and replicative stress and could identify patients at higher risk for toxicity after transplantation. We measured relative telomere length in pretransplant recipient blood samples in 1514 MDS patients and evaluated the association of telomere length with MDS disease characteristics and transplantation outcomes. Shorter telomere length was significantly associated with older age, male sex, somatic mutations that impair the DNA damage response, and more severe pretransplant cytopenias, but not with bone marrow blast count, MDS treatment history, or history of prior cancer therapy. Among 1267 patients ≥40 years old, telomere length in the shortest quartile was associated with inferior survival (P < .001) because of a high risk of nonrelapse mortality (NRM; P = .001) after adjusting for significant clinical and genetic variables. The adverse impact of shorter telomeres on NRM was independent of recipient comorbidities and was observed selectively among patients receiving more intensive conditioning, including myeloablative regimens and higher dose melphalan-based reduced-intensity regimens. The effect of shorter telomeres on NRM was prominent among patients who developed severe acute graft-versus-host disease, suggesting that short telomere length may limit regenerative potential of mucosal tissues after acute injury. MDS patients with shorter telomere length, who have inferior survival driven by excess toxicity, could be considered for strategies focused on minimizing toxic effects of transplantation.
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http://dx.doi.org/10.1182/blood.2020005397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770569PMC
December 2020

Cancer therapy shapes the fitness landscape of clonal hematopoiesis.

Nat Genet 2020 11 26;52(11):1219-1226. Epub 2020 Oct 26.

Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

Acquired mutations are pervasive across normal tissues. However, understanding of the processes that drive transformation of certain clones to cancer is limited. Here we study this phenomenon in the context of clonal hematopoiesis (CH) and the development of therapy-related myeloid neoplasms (tMNs). We find that mutations are selected differentially based on exposures. Mutations in ASXL1 are enriched in current or former smokers, whereas cancer therapy with radiation, platinum and topoisomerase II inhibitors preferentially selects for mutations in DNA damage response genes (TP53, PPM1D, CHEK2). Sequential sampling provides definitive evidence that DNA damage response clones outcompete other clones when exposed to certain therapies. Among cases in which CH was previously detected, the CH mutation was present at tMN diagnosis. We identify the molecular characteristics of CH that increase risk of tMN. The increasing implementation of clinical sequencing at diagnosis provides an opportunity to identify patients at risk of tMN for prevention strategies.
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http://dx.doi.org/10.1038/s41588-020-00710-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891089PMC
November 2020

Inherited causes of clonal haematopoiesis in 97,691 whole genomes.

Nature 2020 10 14;586(7831):763-768. Epub 2020 Oct 14.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Age is the dominant risk factor for most chronic human diseases, but the mechanisms through which ageing confers this risk are largely unknown. The age-related acquisition of somatic mutations that lead to clonal expansion in regenerating haematopoietic stem cell populations has recently been associated with both haematological cancer and coronary heart disease-this phenomenon is termed clonal haematopoiesis of indeterminate potential (CHIP). Simultaneous analyses of germline and somatic whole-genome sequences provide the opportunity to identify root causes of CHIP. Here we analyse high-coverage whole-genome sequences from 97,691 participants of diverse ancestries in the National Heart, Lung, and Blood Institute Trans-omics for Precision Medicine (TOPMed) programme, and identify 4,229 individuals with CHIP. We identify associations with blood cell, lipid and inflammatory traits that are specific to different CHIP driver genes. Association of a genome-wide set of germline genetic variants enabled the identification of three genetic loci associated with CHIP status, including one locus at TET2 that was specific to individuals of African ancestry. In silico-informed in vitro evaluation of the TET2 germline locus enabled the identification of a causal variant that disrupts a TET2 distal enhancer, resulting in increased self-renewal of haematopoietic stem cells. Overall, we observe that germline genetic variation shapes haematopoietic stem cell function, leading to CHIP through mechanisms that are specific to clonal haematopoiesis as well as shared mechanisms that lead to somatic mutations across tissues.
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http://dx.doi.org/10.1038/s41586-020-2819-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944936PMC
October 2020

Fitness Landscape of Clonal Hematopoiesis Under Selective Pressure of Immune Checkpoint Blockade.

JCO Precis Oncol 2020 9;4. Epub 2020 Sep 9.

Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

Purpose: Conventional cytotoxic therapies increase the risk of clonal hematopoiesis and select for -mutant clones, which carry a high risk for transformation to therapy-related myelodysplastic neoplasms. In contrast, the effect of immune checkpoint blockade (ICB) on clonal hematopoiesis is unknown.

Methods: Paired peripheral-blood samples taken before and after treatment with ICB were obtained for 91 patients with either cutaneous melanoma or basal cell carcinoma. Error-corrected sequencing of a targeted panel of genes recurrently mutated in clonal hematopoiesis was performed on peripheral-blood genomic DNA.

Results: The average interval between acquisition of the paired samples was 180 days. Forty-one percent of the patients had clonal hematopoiesis at a variant allele frequency (VAF) > 0.01 in the pretreatment sample. There was near-complete agreement in the distribution and burden of clonal hematopoiesis mutations in the paired blood samples, with 87 of 88 mutations identified across the cohort present in paired samples, regardless of the duration between sample collection. The VAF in the paired samples also showed a high correlation, with an = 0.95 ( < .0001). In contrast to cytotoxic therapy, exposure to ICB did not lead to selection of - or -mutant clones. However, consistent with the known effects of DNA-damaging therapy, we identified one patient who had eight unique mutations in the posttreatment blood sample after receiving two courses of radiation therapy.

Conclusion: There was no expansion of hematopoietic clones or selection for clones at high risk for malignant transformation in patients who received ICB, observations that warrant further validation in larger cohorts. These findings highlight an important difference between ICB and conventional cytotoxic therapies and their respective impacts on premalignant genetic lesions.
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http://dx.doi.org/10.1200/PO.20.00186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529531PMC
September 2020

Contribution of clonal hematopoiesis to adult-onset hemophagocytic lymphohistiocytosis.

Blood 2020 12;136(26):3051-3055

Department of Medical Oncology, Dana-Farber Cancer Institute.

Adult-onset hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening disease of immune hyperactivation. Unlike pediatric HLH, adult HLH is rarely driven by germline genetic variants. Although numerous precipitating etiologies have been identified, the reason that HLH occurs in only a subset of individuals and how other factors contribute to the disease remains unknown. We hypothesized that clonal hematopoiesis (CH), a state in which somatic mutations in blood cells cause an expanded population of mutant hematopoietic cells and drive an aberrant inflammatory state, could contribute to adult-onset HLH. In a highly annotated cohort of older adults with HLH we found that CH was more prevalent than in control cohorts. Using the adult-onset HLH mouse model in which repeated treatments of the TLR9 agonist, ODN1826, was delivered to the mouse, we observed that macrophages carrying mutations in Tet2, one of the most commonly mutated genes in CH, have an enhanced inflammatory response to TLR9 agonism. Finally, mice carrying Tet2 mutations in the hematopoietic compartment (a common model for CH) displayed an exaggerated response to TLR9 agonism, including worse splenomegaly and anemia. Our data suggest that CH is more common in individuals with adult-onset HLH and can contribute to the pathophysiology of this disease.
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http://dx.doi.org/10.1182/blood.2020008206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770567PMC
December 2020

Targeted Informatics for Optimal Detection, Characterization, and Quantification of FLT3 Internal Tandem Duplications Across Multiple Next-Generation Sequencing Platforms.

J Mol Diagn 2020 09 27;22(9):1162-1178. Epub 2020 Jun 27.

Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts. Electronic address:

Assessment of internal tandem duplications in FLT3 (FLT3-ITDs) and their allelic ratio (AR) is recommended by clinical guidelines for diagnostic workup of acute myeloid leukemia and traditionally performed through capillary electrophoresis (CE). Although significant progress has been made integrating FLT3-ITD detection within contemporary next-generation sequencing (NGS) panels, AR estimation is not routinely part of clinical NGS practice because of inherent biases and challenges. In this study, data from multiple NGS platforms-anchored multiplex PCR (AMP), amplicon [TruSeq Custom Amplicon (TSCA)], and hybrid-capture-were analyzed through a custom algorithm, including platform-specific measures of AR. Sensitivity and specificity of NGS for FLT3-ITD status relative to CE were 100% (42/42) and 99.4% (1076/1083), respectively, by AMP on an unselected cohort and 98.1% (53/54) and 100% (48/48), respectively, by TSCA on a selected cohort. Primer analysis identified criteria for ITDs to escape detection by TSCA, estimated to occur in approximately 9% of unselected ITDs. Allelic fractions under AMP or TSCA were highly correlated to CE, with linear regression slopes near 1 for ITDs not duplicating primers, and systematically underestimated for ITDs duplicating a primer. Bias was alleviated in AMP through simple adjustments. This article provides an approach for targeted computational FLT3-ITD analysis for NGS data from multiple platforms; AMP was found capable of near perfect sensitivity and specificity with relatively accurate estimates of ARs.
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http://dx.doi.org/10.1016/j.jmoldx.2020.06.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7479488PMC
September 2020

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Nat Commun 2020 06 12;11(1):2996. Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.
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http://dx.doi.org/10.1038/s41467-020-16805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293239PMC
June 2020

Stem cell donors should not be screened for clonal hematopoiesis.

Blood Adv 2020 02;4(4):789-792

Division of Hematological Malignancies, Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.

This article has a companion Point by DeZern and Gondek.
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http://dx.doi.org/10.1182/bloodadvances.2019000395DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042999PMC
February 2020

Control of spatially rotating structures in diffractive Kerr cavities.

Opt Express 2019 Oct;27(22):31273-31289

Turing patterns in self-focussing nonlinear optical cavities pumped by beams carrying orbital angular momentum (OAM) are shown to rotate with an angular velocity =2/ on rings of radii . We verify this prediction in 1D models on a ring and for 2D Laguerre-Gaussian and top-hat pumps with OAM. Full control over the angular velocity of the pattern in the range -2/ ≤≤2/ is obtained by using cylindrical vector beam pumps that consist of orthogonally polarized eigenmodes with equal and opposite OAM. Using Poincaré beams that consist of orthogonally polarized eigenmodes with different magnitudes of OAM, the resultant angular velocity is =( + )/ , where , are the OAMs of the eigenmodes, assuming good overlap between the eigenmodes. If there is no, or very little, overlap between the modes then concentric Turing pattern rings, each with angular velocity =2 / will result. This can lead to, for example, concentric, counter-rotating Turing patterns creating an optical peppermill-type structure. Full control over the speeds of multiple rings has potential applications in particle manipulation and stretching, atom trapping, and circular transport of cold atoms and BEC wavepackets.
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http://dx.doi.org/10.1364/OE.27.031273DOI Listing
October 2019

Premature Aging in Young Cancer Survivors.

J Natl Cancer Inst 2019 03;111(3):226-232

Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN.

Advances in early detection, treatment, and supportive care have resulted in an estimated 16 million cancer survivors who are alive in the United States today. Outcomes have notably improved for children with cancer as well as young adults with hematologic malignancies due, in part, to the intensification of cancer treatment, including the use of hematopoietic cell transplantation. Emerging evidence suggests that these cancer survivors are at risk for premature aging, manifesting as early onset of chronic health conditions and a higher risk of mortality compared with the general population. Although the pathophysiology of premature aging in these survivors has not been fully elucidated, emerging concepts in aging research could help shed light on this phenomenon. Longitudinal studies are needed to better characterize aging in these survivors, setting the stage for much-needed interventions to halt the trajectory of accelerated aging. These efforts will be enhanced through collaborations between translational researchers, clinical oncologists, primary care providers, geriatricians, patient caretakers, and other stakeholders committed to improving the lives of the growing population of survivors.
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http://dx.doi.org/10.1093/jnci/djy229DOI Listing
March 2019

High -mutant allele burden at diagnosis predicts unfavorable outcomes in de novo AML.

Blood 2018 06 3;131(25):2816-2825. Epub 2018 May 3.

Department of Pathology, Brigham and Women's Hospital, Boston, MA.

Acute myeloid leukemia (AML) with mutated is a newly recognized separate entity in the revised 2016 World Health Organization classification and is associated with a favorable prognosis. Although previous studies have evaluated in a binary fashion, little is known about the significance of its mutant allele burden at diagnosis, nor has the effect of comutations (other than ) been extensively evaluated. We retrospectively used targeted sequencing data from 109 patients with de novo AML with mutated to evaluate the potential significance of variant allele frequency (VAF), comutations, and clinical parameters with regard to patient outcomes. We observed that high VAF (uppermost quartile) correlated with shortened overall survival (median, 12.1 months vs not reached; < .0001) as well as event-free survival (median, 7.5 vs 65.44 months; < .0001) compared with the other -mutated cases. In both univariate and multivariable analyses, high VAF had a particularly adverse prognostic effect in the subset of patients treated with stem-cell transplantation in first remission ( = .0004) and in patients with mutated ( < .0001). Our findings indicate that the prognostic effect of mutation in de novo AML may be influenced by the relative abundance of the mutated allele.
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http://dx.doi.org/10.1182/blood-2018-01-828467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6265642PMC
June 2018

New Insights from Studies of Clonal Hematopoiesis.

Clin Cancer Res 2018 10 27;24(19):4633-4642. Epub 2018 Apr 27.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.

Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater, it is termed "clonal hematopoiesis of indeterminate potential" (CHIP). CHIP has a 0.5% to 1% risk per year of progression to hematologic neoplasia, and increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a proinflammatory interaction between clonally derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, whereas CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a mutation is present. However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemotherapy are poorly defined. In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state. .
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http://dx.doi.org/10.1158/1078-0432.CCR-17-3044DOI Listing
October 2018

Association of mutations with morphological dysplasia in acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities.

Haematologica 2018 04 11;103(4):626-633. Epub 2018 Jan 11.

Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.

Despite improvements in our understanding of the molecular basis of acute myeloid leukemia (AML), the association between genetic mutations with morphological dysplasia remains unclear. In this study, we evaluated and scored dysplasia in bone marrow (BM) specimens from 168 patients with AML; none of these patients had cytogenetic abnormalities according to the 2016 World Health Organization Classification. We then performed targeted sequencing of diagnostic BM aspirates for recurrent mutations associated with myeloid malignancies. We found that cohesin pathway mutations [q (FDR-adjusted )=0.046] were associated with a higher degree of megakaryocytic dysplasia and mutations were marginally associated with greater myeloid lineage dysplasia (q=0.052). Frequent megakaryocytes with separated nuclear lobes were more commonly seen among cases with cohesin pathway mutations (q=0.010) and specifically in those with mutations (q=0.010), as well as mutations (q=0.022 when considering the presence of any no megakaryocytes with separated nuclear lobes). RAS pathway mutations (q=0.006) and (q=0.006) were significantly more frequent in cases without evaluable erythroid cells. In univariate analysis of the 153 patients treated with induction chemotherapy, mutations were associated with longer event-free survival (EFS) (=0.042), while (=0.042), (=0.040), frequent micromegakaryocytes (=0.018) and presence of a subclone (=0.002) were associated with shorter EFS. In multivariable modeling, was associated with longer EFS, while presence of a subclone and frequent micromegakaryocytes remained significantly associated with shorter EFS.
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http://dx.doi.org/10.3324/haematol.2017.181842DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5865424PMC
April 2018

Clonal Hematopoiesis and Risk of Atherosclerotic Cardiovascular Disease.

N Engl J Med 2017 07 21;377(2):111-121. Epub 2017 Jun 21.

From the Department of Medicine, Division of Hematology, Brigham and Women's Hospital (S.J., A.J.S., M.M.) and Harvard Medical School (B.L.E.), the Department of Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital (E.S.) and Harvard Medical School (G.K.S., P.L.), the Department of Pathology (S.J.) and the Center for Genomic Medicine (P.N., S.K.), Massachusetts General Hospital, the Department of Medicine, Division of Cardiology, and Cardiovascular Research Center (P.N., S.K.), and the Department of Medicine (A.G.B.), Massachusetts General Hospital and Harvard Medical School, and the Departments of Medical Oncology (C.J.G.) and Biostatistics and Computational Biology (D.N.), Dana-Farber Cancer Institute, Boston, and the Program in Medical and Population Genetics, Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge (P.N., A.G.B., N.G., S.G., S.K.) - all in Massachusetts; the Department of Cardiology, University Hospital, Parma, Italy (D.A.); the Department of Medicine, Division of Cardiology, Mt. Sinai School of Medicine, New York (U.B., R.M., V.F.); Centro Nacional de Investigaciones Cardiovasculares Carlos III, Madrid (V.F.); Medical Research Council-British Heart Foundation Cardiovascular Epidemiology Unit and National Institute for Health Research Blood and Transplant Research Unit in Donor Health and Genomics, Department of Public Health and Primary Care, and the British Heart Foundation, Cambridge Centre of Excellence, Department of Medicine, University of Cambridge, Cambridge (J.D.), and the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton (J.D.) - both in the United Kingdom; the Center for Non-Communicable Diseases, Karachi, Pakistan (P.F., D.S.); the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia (D.S.); and the Department of Clinical Sciences Malmö, Lund University, Lund, Sweden (O.M.).

Background: Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.

Methods: We used whole-exome sequencing to detect the presence of CHIP in peripheral-blood cells and associated such presence with coronary heart disease using samples from four case-control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.

Results: In nested case-control analyses from two prospective cohorts, carriers of CHIP had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case-control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.

Conclusions: The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice. (Funded by the National Institutes of Health and others.).
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http://dx.doi.org/10.1056/NEJMoa1701719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6717509PMC
July 2017

Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma.

J Clin Oncol 2017 May 9;35(14):1598-1605. Epub 2017 Jan 9.

Christopher J. Gibson, R. Coleman Lindsley, Brenton G. Mar, Jiantao Shi, Ann S. Lacasce, Arnold S. Freedman, David C. Fisher, Eric Jacobsen, Philippe Armand, Edwin P. Alyea, John Koreth, Vincent Ho, Robert J. Soiffer, Joseph H. Antin, Jerome Ritz, Sarah Nikiforow, Franziska Michor, and Donna Neuberg, Dana-Farber Cancer Institute; Jiantao Shi and Franziska Michor, Harvard T.H. Chan School of Public Health; Siddhartha Jaiswal, Elizabeth A. Morgan, and Benjamin L. Ebert, Brigham and Women's Hospital, Boston; Benjamin L. Ebert, Broad Institute, Cambridge, MA; Vatche Tchekmedyian, Memorial Sloan Kettering Cancer Center, New York, NY; Alysia Bosworth, Anita Bansal, and Stephen J. Forman, City of Hope National Medical Center, Duarte, CA; and Liton Francisco, Jianbo He, Ravi Bhatia, and Smita Bhatia, University of Alabama at Birmingham, Birmingham, AL.

Purpose Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition characterized by somatic mutations in the blood of otherwise healthy adults. We hypothesized that in patients undergoing autologous stem-cell transplantation (ASCT) for lymphoma, CHIP at the time of ASCT would be associated with an increased risk of myelodysplastic syndrome and acute myeloid leukemia, collectively termed therapy-related myeloid neoplasm (TMN), and other adverse outcomes. Methods We performed whole-exome sequencing on pre- and post-ASCT samples from 12 patients who developed TMN after autologous transplantation for Hodgkin lymphoma or non-Hodgkin lymphoma and targeted sequencing on cryopreserved aliquots of autologous stem-cell products from 401 patients who underwent ASCT for non-Hodgkin lymphoma between 2003 and 2010. We assessed the effect of CHIP at the time of ASCT on subsequent outcomes, including TMN, cause-specific mortality, and overall survival. Results For six of 12 patients in the exome sequencing cohort, mutations found in the TMN specimen were also detectable in the pre-ASCT specimen. In the targeted sequencing cohort, 120 patients (29.9%) had CHIP at the time of ASCT, which was associated with an increased rate of TMN (10-year cumulative incidence, 14.1% v 4.3% for those with and without CHIP, respectively; P = .002). Patients with CHIP had significantly inferior overall survival compared with those without CHIP (10-year overall survival, 30.4% v 60.9%, respectively; P < .001), including increased risk of death from TMN and cardiovascular disease. Conclusion In patients undergoing ASCT for lymphoma, CHIP at the time of transplantation is associated with inferior survival and increased risk of TMN.
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http://dx.doi.org/10.1200/JCO.2016.71.6712DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5455707PMC
May 2017

The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia.

Nat Rev Cancer 2017 01 11;17(1):5-19. Epub 2016 Nov 11.

Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.

Myelodysplastic syndrome (MDS) is a clonal disease that arises from the expansion of mutated haematopoietic stem cells. In a spectrum of myeloid disorders ranging from clonal haematopoiesis of indeterminate potential (CHIP) to secondary acute myeloid leukaemia (sAML), MDS is distinguished by the presence of peripheral blood cytopenias, dysplastic haematopoietic differentiation and the absence of features that define acute leukaemia. More than 50 recurrently mutated genes are involved in the pathogenesis of MDS, including genes that encode proteins involved in pre-mRNA splicing, epigenetic regulation and transcription. In this Review we discuss the molecular processes that lead to CHIP and further clonal evolution to MDS and sAML. We also highlight the ways in which these insights are shaping the clinical management of MDS, including classification schemata, prognostic scoring systems and therapeutic approaches.
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http://dx.doi.org/10.1038/nrc.2016.112DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5470392PMC
January 2017

CLINICAL PROBLEM-SOLVING. A Bruising Loss.

N Engl J Med 2016 Jul;375(1):76-81

From the Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston.

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http://dx.doi.org/10.1056/NEJMcps1500127DOI Listing
July 2016

Optical Rogue Waves in Vortex Turbulence.

Phys Rev Lett 2016 Jan 27;116(4):043903. Epub 2016 Jan 27.

SUPA and Department of Physics, University of Strathclyde, Glasgow G4 0NG, Scotland, United Kingdom.

We present a spatiotemporal mechanism for producing 2D optical rogue waves in the presence of a turbulent state with creation, interaction, and annihilation of optical vortices. Spatially periodic structures with bound phase lose stability to phase unbound turbulent states in complex Ginzburg-Landau and Swift-Hohenberg models with external driving. When the pumping is high and the external driving is low, synchronized oscillations are unstable and lead to spatiotemporal vortex-mediated turbulence with high excursions in amplitude. Nonlinear amplification leads to rogue waves close to turbulent optical vortices, where the amplitude tends to zero, and to probability density functions (PDFs) with long tails typical of extreme optical events.
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http://dx.doi.org/10.1103/PhysRevLett.116.043903DOI Listing
January 2016
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