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American Journal of Hematology May 2023Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied... (Review)
Review
DISEASE OVERVIEW
Primary myelofibrosis (PMF) is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation that is often but not always accompanied by JAK2, CALR, or MPL mutations; additional features include bone marrow reticulin/collagen fibrosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, risk of leukemic progression, and shortened survival.
DIAGNOSIS
Bone marrow examination with cytogenetic and mutation studies provides integrated diagnostic information; presence of JAK2, CALR or MPL mutation is expected but not required.
NEW CLASSIFICATION SYSTEM
The International Consensus Classification distinguishes "prefibrotic" from "overtly fibrotic" PMF; the former might mimic essential thrombocythemia (ET) in its presentation. Approximately 15% of patients with ET or polycythemia vera (PV) might progress into post-ET/PV MF.
MUTATIONS
SRSF2, ASXL1, and U2AF1-Q157 mutations predict inferior survival in PMF; RAS/CBL mutations predict resistance to ruxolitinib therapy. Type 1/like CALR mutation is associated with superior survival.
KARYOTYPE
Very high-risk abnormalities include -7, inv (3), i(17q), +21, +19, 12p- and 11q-. Favorable risk abnormalities include normal karyotype or isolated +9, 13q-, 20q-, 1q abnormalities and loss of Y chromosome.
RISK STRATIFICATION
Contemporary prognostic systems include GIPSS (genetically-inspired prognostic scoring system) and MIPSS70+ version 2.0 (MIPSSv2; mutation-and karyotype-enhanced international prognostic scoring system). GIPSS is based exclusively on mutations and karyotype; MIPSSv2 includes, in addition, clinical risk factors.
RISK-ADAPTED THERAPY
Observation alone is advised for MIPSSv2 "low" and "very low" risk disease (estimated 10-year survival 56%-92%); allogeneic hematopoietic stem cell transplant (AHSCT) is the preferred treatment of choice for "very high" and "high" risk disease (estimated 10-year survival 0-13%), as well as in carefully selected patients with intermediate-risk disease (estimated 10-year survival 30%). Drug therapy in MF is currently palliative and targets anemia, splenomegaly, and constitutional symptoms. JAK2 INHIBITORS: Ruxolitinib, fedratinib, and pacritinib are FDA approved and respectfully utilized in patients failing treatment with hydroxyurea, ruxolitinib, or with platelet count <50 × 10 (9)/L. Momelotinib is another JAK2 inhibitor that is poised for approval sometime in 2023 and has shown erythropoietic benefits, in addition to affecting spleen and symptom responses.
OTHER TREATMENT MODALITIES
Splenectomy is considered for drug-refractory splenomegaly and involved field radiotherapy for non-hepatosplenic EMH and extremity bone pain.
NEW DIRECTIONS
New agents, alone or in combination with ruxolitinib, are currently under clinical trial investigation (ClinicalTrials.gov) and preliminary results were presented at the 2022 ASH annual meeting and highlighted in the current review.
Topics: Humans; Primary Myelofibrosis; Splenomegaly; Polycythemia Vera; Pyrazoles; Thrombocythemia, Essential; Mutation; Janus Kinase 2
PubMed: 36680511
DOI: 10.1002/ajh.26857 -
Cell Jun 2022Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly...
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system (CNS). Bone marrow hematopoietic stem and progenitor cells (HSPCs) rapidly sense immune activation, yet their potential interplay with autoreactive T cells in MS is unknown. Here, we report that bone marrow HSPCs are skewed toward myeloid lineage concomitant with the clonal expansion of T cells in MS patients. Lineage tracing in experimental autoimmune encephalomyelitis, a mouse model of MS, reveals remarkable bone marrow myelopoiesis with an augmented output of neutrophils and Ly6C monocytes that invade the CNS. We found that myelin-reactive T cells preferentially migrate into the bone marrow compartment in a CXCR4-dependent manner. This aberrant bone marrow myelopoiesis involves the CCL5-CCR5 axis and augments CNS inflammation and demyelination. Our study suggests that targeting the bone marrow niche presents an avenue to treat MS and other autoimmune disorders.
Topics: Animals; Bone Marrow; Encephalomyelitis, Autoimmune, Experimental; Hematopoiesis; Humans; Mice; Mice, Inbred C57BL; Multiple Sclerosis
PubMed: 35709748
DOI: 10.1016/j.cell.2022.05.020 -
Leukemia Oct 2022Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of... (Review)
Review
Nucleophosmin 1 (NPM1) is a nucleus-cytoplasmic shuttling protein which is predominantly located in the nucleolus and exerts multiple functions, including regulation of centrosome duplication, ribosome biogenesis and export, histone assembly, maintenance of genomic stability and response to nucleolar stress. NPM1 mutations are the most common genetic alteration in acute myeloid leukemia (AML), detected in about 30-35% of adult AML and more than 50% of AML with normal karyotype. Because of its peculiar molecular and clinico-pathological features, including aberrant cytoplasmic dislocation of the NPM1 mutant and wild-type proteins, lack of involvement in driving clonal hematopoiesis, mutual exclusion with recurrent cytogenetic abnormalities, association with unique gene expression and micro-RNA profiles and high stability at relapse, NPM1-mutated AML is regarded as a distinct genetic entity in the World Health Organization (WHO) classification of hematopoietic malignancies. Starting from the structure and functions of NPM1, we provide an overview of the potential targeted therapies against NPM1-mutated AML and discuss strategies aimed at interfering with the oligomerization (compound NSC348884) and the abnormal traffic of NPM1 (avrainvillamide, XPO1 inhibitors) as well as at inducing selective NPM1-mutant protein degradation (ATRA/ATO, deguelin, (-)-epigallocatechin-3-gallate, imidazoquinoxaline derivatives) and at targeting the integrity of nucleolar structure (actinomycin D). We also discuss the current therapeutic results obtained in NPM1-mutated AML with the BCL-2 inhibitor venetoclax and the preliminary clinical results using menin inhibitors targeting HOX/MEIS1 expression. Finally, we review various immunotherapeutic approaches in NPM1-mutated AML, including immune check-point inhibitors, CAR and TCR T-cell-based therapies against neoantigens created by the NPM1 mutations.
Topics: Adult; Dactinomycin; Histones; Humans; Leukemia, Myeloid, Acute; Mutation; Nuclear Proteins; Nucleophosmin; Proto-Oncogene Proteins c-bcl-2; RNA; Receptors, Antigen, T-Cell
PubMed: 36008542
DOI: 10.1038/s41375-022-01666-2 -
Cell Mar 2019Lineage tracing provides key insights into the fate of individual cells in complex organisms. Although effective genetic labeling approaches are available in model...
Lineage tracing provides key insights into the fate of individual cells in complex organisms. Although effective genetic labeling approaches are available in model systems, in humans, most approaches require detection of nuclear somatic mutations, which have high error rates, limited scale, and do not capture cell state information. Here, we show that somatic mutations in mtDNA can be tracked by single-cell RNA or assay for transposase accessible chromatin (ATAC) sequencing. We leverage somatic mtDNA mutations as natural genetic barcodes and demonstrate their utility as highly accurate clonal markers to infer cellular relationships. We track native human cells both in vitro and in vivo and relate clonal dynamics to gene expression and chromatin accessibility. Our approach should allow clonal tracking at a 1,000-fold greater scale than with nuclear genome sequencing, with simultaneous information on cell state, opening the way to chart cellular dynamics in human health and disease.
Topics: Base Sequence; Cell Lineage; Chromatin; Colorectal Neoplasms; DNA, Mitochondrial; Genomics; HEK293 Cells; Hematopoietic Stem Cells; High-Throughput Nucleotide Sequencing; Humans; Mitochondria; Mutation; Single-Cell Analysis; Transposases
PubMed: 30827679
DOI: 10.1016/j.cell.2019.01.022 -
JAMA Cardiology Feb 2023Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia... (Review)
Review
IMPORTANCE
Recent clinical and imaging studies underscore that major adverse cardiac events (MACE) outcomes are associated not solely with severe coronary obstructions (ischemia hypothesis or stenosis hypothesis), but with the plaque burden along the entire coronary tree. New research clarifies the pathobiologic mechanisms responsible for plaque development/progression/destabilization leading to MACE (plaque hypothesis), but the translation of these insights to clinical management strategies has lagged. This narrative review elaborates the plaque hypothesis and explicates the current understanding of underlying pathobiologic mechanisms, the provocative destabilizing influences, the diagnostic and therapeutic implications, and their actionable clinical management approaches to optimize the management of patients with chronic coronary disease.
OBSERVATIONS
Clinical trials of management strategies for patients with chronic coronary artery disease demonstrate that while MACE rate increases progressively with the anatomic extent of coronary disease, revascularization of the ischemia-producing obstruction does not forestall MACE. Most severely obstructive coronary lesions often remain quiescent and seldom destabilize to cause a MACE. Coronary lesions that later provoke acute myocardial infarction often do not narrow the lumen critically. Invasive and noninvasive imaging can identify the plaque anatomic characteristics (plaque burden, plaque topography, lipid content) and local hemodynamic/biomechanical characteristics (endothelial shear stress, plaque structural stress, axial plaque stress) that can indicate the propensity of individual plaques to provoke a MACE.
CONCLUSIONS AND RELEVANCE
The pathobiologic construct concerning the culprit region of a plaque most likely to cause a MACE (plaque hypothesis), which incorporates multiple convergent plaque features, informs the evolution of a new management strategy capable of identifying the high-risk portion of plaque wherever it is located along the course of the coronary artery. Ongoing investigations of high-risk plaque features, coupled with technical advances to enable prognostic characterization in real time and at the point of care, will soon enable evaluation of the entire length of the atheromatous coronary artery and broaden the target(s) of our therapeutic intervention to include all regions of the plaque (both flow limiting and nonflow limiting).
Topics: Humans; Coronary Artery Disease; Plaque, Atherosclerotic; Myocardial Ischemia; Myocardial Infarction; Risk Factors
PubMed: 36515941
DOI: 10.1001/jamacardio.2022.3926 -
JAMA Jul 2023The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully...
IMPORTANCE
The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.
OBJECTIVE
To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.
DESIGN, SETTING, AND PARTICIPANTS
This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.
INTERVENTIONS
Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106).
MAIN OUTCOME MEASURES
The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.
RESULTS
Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.
CONCLUSIONS
In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02993406.
Topics: Humans; Female; Aged; Male; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Cardiovascular Diseases; Myocardial Infarction; Stroke; Primary Prevention
PubMed: 37354546
DOI: 10.1001/jama.2023.9696 -
Nature Medicine Nov 2021Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic...
Clonal hematopoiesis (CH) results from somatic genomic alterations that drive clonal expansion of blood cells. Somatic gene mutations associated with hematologic malignancies detected in hematopoietic cells of healthy individuals, referred to as CH of indeterminate potential (CHIP), have been associated with myeloid malignancies, while mosaic chromosomal alterations (mCAs) have been associated with lymphoid malignancies. Here, we analyzed CHIP in 55,383 individuals and autosomal mCAs in 420,969 individuals with no history of hematologic malignancies in the UK Biobank and Mass General Brigham Biobank. We distinguished myeloid and lymphoid somatic gene mutations, as well as myeloid and lymphoid mCAs, and found both to be associated with risk of lineage-specific hematologic malignancies. Further, we performed an integrated analysis of somatic alterations with peripheral blood count parameters to stratify the risk of incident myeloid and lymphoid malignancies. These genetic alterations can be readily detected in clinical sequencing panels and used with blood count parameters to identify individuals at high risk of developing hematologic malignancies.
Topics: Blood Cell Count; Chromosome Aberrations; Clonal Hematopoiesis; Hematologic Neoplasms; Hematopoietic Stem Cells; Humans
PubMed: 34663986
DOI: 10.1038/s41591-021-01521-4 -
Cancer Discovery Jan 2022Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A () are...
Clonal hematopoiesis is a prevalent age-related condition associated with a greatly increased risk of hematologic disease; mutations in DNA methyltransferase 3A () are the most common driver of this state. variants occur across the gene with some particularly associated with malignancy, but the functional relevance and mechanisms of pathogenesis of the majority of mutations are unknown. Here, we systematically investigated the methyltransferase activity and protein stability of 253 disease-associated mutations, and found that 74% were loss-of-function mutations. Half of these variants exhibited reduced protein stability and, as a class, correlated with greater clonal expansion and acute myeloid leukemia development. We investigated the mechanisms underlying the instability using a CRISPR screen and uncovered regulated destruction of DNMT3A mediated by the DCAF8 E3 ubiquitin ligase adaptor. We establish a new paradigm to classify novel variants that has prognostic and potential therapeutic significance for patients with hematologic disease. SIGNIFICANCE: DNMT3A has emerged as the most important epigenetic regulator and tumor suppressor in the hematopoietic system. Our study represents a systematic and high-throughput method to characterize the molecular impact of missense mutations and the discovery of a regulated destruction mechanism of DNMT3A offering new prognostic and future therapeutic avenues...
Topics: Animals; DNA Methyltransferase 3A; HEK293 Cells; Humans; Leukemia, Myeloid, Acute; Leukocytes, Mononuclear; Mice; Mutation, Missense; Ubiquitin-Protein Ligases
PubMed: 34429321
DOI: 10.1158/2159-8290.CD-21-0560 -
Seminars in Hematology Apr 2019Acute myeloid leukemia (AML) was one of the first cancers to be sequenced at the level of the whole genome. Molecular profiling of AML through targeted sequencing panels... (Review)
Review
Acute myeloid leukemia (AML) was one of the first cancers to be sequenced at the level of the whole genome. Molecular profiling of AML through targeted sequencing panels and cytogenetics has become a mainstay in risk-stratifying AML patients and guiding clinicians toward optimal therapies for their patients. The extensive high-resolution genomic data generated to characterize AML have been instrumental in revealing the tremendous biological complexity of the disease, dictated in part by mutational, clonal, and epigenetic heterogeneity. This is further complicated by the antecedent nonleukemic state of clonal hematopoiesis that nevertheless is associated with an increased risk of developing a hematologic malignancy and with a greater risk of mortality from ischemic cardiovascular disease. Here in this review, we discuss developments in the field of AML biology and therapeutics, with a focus on advances in our understanding of how genetic and epigenetic determinants of AML have influenced prognostication and recent shifts in treatment paradigms, particularly within the context of precision oncology, for this highly complex group of hematologic malignancies.
Topics: Epigenesis, Genetic; Epigenomics; Humans; Leukemia, Myeloid, Acute
PubMed: 30926095
DOI: 10.1053/j.seminhematol.2018.08.001 -
Nature Medicine Oct 2021Germline SAMD9 and SAMD9L mutations (SAMD9/9L) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a...
Germline SAMD9 and SAMD9L mutations (SAMD9/9L) predispose to myelodysplastic syndromes (MDS) with propensity for somatic rescue. In this study, we investigated a clinically annotated pediatric MDS cohort (n = 669) to define the prevalence, genetic landscape, phenotype, therapy outcome and clonal architecture of SAMD9/9L syndromes. In consecutively diagnosed MDS, germline SAMD9/9L accounted for 8% and were mutually exclusive with GATA2 mutations present in 7% of the cohort. Among SAMD9/9L cases, refractory cytopenia was the most prevalent MDS subtype (90%); acquired monosomy 7 was present in 38%; constitutional abnormalities were noted in 57%; and immune dysfunction was present in 28%. The clinical outcome was independent of germline mutations. In total, 67 patients had 58 distinct germline SAMD9/9L clustering to protein middle regions. Despite inconclusive in silico prediction, 94% of SAMD9/9L suppressed HEK293 cell growth, and mutations expressed in CD34 cells induced overt cell death. Furthermore, we found that 61% of SAMD9/9L patients underwent somatic genetic rescue (SGR) resulting in clonal hematopoiesis, of which 95% was maladaptive (monosomy 7 ± cancer mutations), and 51% had adaptive nature (revertant UPD7q, somatic SAMD9/9L). Finally, bone marrow single-cell DNA sequencing revealed multiple competing SGR events in individual patients. Our findings demonstrate that SGR is common in SAMD9/9L MDS and exemplify the exceptional plasticity of hematopoiesis in children.
Topics: Adolescent; Bone Marrow Cells; Child; Child, Preschool; Clonal Evolution; Clonal Hematopoiesis; Female; GATA2 Transcription Factor; Germ-Line Mutation; HEK293 Cells; High-Throughput Nucleotide Sequencing; Humans; Infant; Intracellular Signaling Peptides and Proteins; Kaplan-Meier Estimate; Male; Myelodysplastic Syndromes; Single-Cell Analysis; Tumor Suppressor Proteins
PubMed: 34621053
DOI: 10.1038/s41591-021-01511-6