Effect of clonal hematopoiesis in remission on hematopoiesis recovery in patients with NPM1 mutated acute myeloid leukemia after chemotherapy / 中华血液学杂志

Objective: To investigate the effect of clonal hematopoiesis (CH) in remission on hematopoiesis recovery in patients with NPM1 mutated acute myeloid leukemia (AML) after chemotherapy. Methods: Retrospective analysis was performed on 86 patients with NPM1(mut) AML newly diagnosed and treated in the First Affiliated Hospital of Soochow University between July 2016 and June 2019. Their clinical data and NGS test results at diagnosis were analyzed. Moreover, bone marrow samples in remission were tested using Sanger sequencing. The log-rank test was used to analyze the difference in hematopoietic recovery, and Cox proportional hazard models were used to analyze the prognostic factors affecting hematopoietic recovery. Results: The median age of the 86 NPM1(mut) AML patients was 50 years (15-69 years). There were 39 males and 47 females. Forty-one patients were induced with intensity chemotherapy ("7 + 3"), whereas 45 patients were treated with low-dose cytarabine-based induction chemotherapy. At diagnosis, The most common mutations in the patients were FLT3, DNMT3A, TET2, and IDH1/IDH2 mutations. CH-associated mutations persisted in 21 patients during remission, and the mutations were DNMT3A, TET2, ASXL1, and IDH1/IDH2. The recovery time of neutrophils in patients with CH-associated mutations in remission was consistent with that in patients without CH in remission (P=0.282) but the recovery time of platelets in patients with CH in remission was significantly longer[26 (95% CI 21-32) days vs 25 (95% CI 23-26) days, P=0.032]. Furthermore, univariate analysis indicated that age, induced chemotherapy program, and CH in remission were risk factors for platelet recovery, whereas multivariate analysis indicated that induced chemotherapy program and CH in remission were independent risk factors for platelet recovery (HR=0.454, P=0.001 and HR=0.520, P=0.027, respectively) . Conclusion: CH in remission delays the hematopoietic recovery of patients with NPM1(mut) AML after chemotherapy.

Research Progress on Gene Mutation and CHIP in Pathogenesis of MDS --Review / 中国实验血液学杂志

With the development of molecular biology techniques, the people's understanding of myelodysplastic syndromes (MDS) has greatly improved, a heterogeneous hematopoietic pre-malignant disorder of the stem cells. Gene mutations include RNA splicing, DNA methylation, chromosome modification, transcription factors, signal transduction kinases, RAS pathways, cohesion complexes, DNA repair, etc. Gene mutation is the determinant of diagnostic typing and therapeutic efficacy of MDS. The new concepts of CHIP and ICUS have aroused people's attention to the elderly patients with clonal hematopoiesis and non-clonal cytopenia but without MDS characteristics, who have the possibility of high-risk transformation to MDS and leukemia. In order to better understand the pathogenesis of MDS, the significance of gene mutations, CHIP and ICUS in the diagnosis and prognosis of MDS were reviewed in this paper.

Effect of donor clonal hematopoiesis on allogeneic hematopoietic stem cell transplantation / 白血病·淋巴瘤

Clonal hematopoiesis (CH) refers to the clonal expansion of hematopoietic stem/progenitor cells in some individuals with normal blood indexes. The incidence of CH increases with age, reflecting the decline of the hematopoietic and potential clonal evolution to a certain extent. In recent years, an increasing number of studies have shown that donor CH is an unfavorable factor affecting transplantation, graft-versus-host disease and donor cell leukemia after allogeneic hematopoietic stem cell transplantation. Emphasis on and identification of donor CH can optimize donor selection and help transplant patients benefit more. This article introduces the relevant research progress in combination with the content of the 63rd American Society of Hematology Annual Meeting.

Aging-elevated inflammation promotes DNMT3A R878H-driven clonal hematopoiesis

Aging-elevated DNMT3A R882H-driven clonal hematopoiesis (CH) is a risk factor for myeloid malignancies remission and overall survival. Although some studies were conducted to investigate this phenomenon, the exact mechanism is still under debate. In this study, we observed that DNMT3A R878H bone marrow cells (human allele: DNMT3A R882H) displayed enhanced reconstitution capacity in aged bone marrow milieu and upon inflammatory insult. DNMT3A R878H protects hematopoietic stem and progenitor cells from the damage induced by chronic inflammation, especially TNFα insults. Mechanistically, we identified that RIPK1-RIPK3-MLKL-mediated necroptosis signaling was compromised in R878H cells in response to proliferation stress and TNFα insults. Briefly, we elucidated the molecular mechanism driving DNMT3A R878H-based clonal hematopoiesis, which raises clinical value for treating DNMT3A R882H-driven clonal hematopoiesis and myeloid malignancies with aging.

Research Progress of Clonal Hematopoiesis of Indeterminate Potential in Multiple Myeloma --Review / 中国实验血液学杂志

With the progress of medical technology, cloning hematopoietic was found to be widely exist in normal people. Because of its clinical significance and prognosis is unclear, it is named clonal hematopoiesis of indeterminate potential(CHIP), which has been detected in blood diseases such as myelodysplastic syndrome and lymphoma, and proven to be related to poor prognosis. Recently, CHIP has been also detected in patients with multiple myeloma (MM). In this article, the definition and influencing factors of CHIP, clinical significance, prognosis and treatment in MM were reviewed.

Clonal hematopoiesis of indeterminate potential and aging / 中华老年医学杂志

Clonal hematopoiesis with indeterminant potential(CHIP)is defined as the proportion of detectable clonal hematopoietic cells in peripheral blood exceeding 2% and without confirmed hematologic malignancy.CHIP could increase the risk of malignant diseases through changes in DNA damage response, transcriptional programming and epigenetic modification.The incidence of malignant tumors in the blood system is significantly higher in the CHIP patients than healthy person.In addition, CHIP represents a negative factor associated with aging.Recent studies have found that the incidences of infections, anemia, heart failure, thrombotic events, and tumors of the blood system in CHIP carriers were significantly increased.Starting with the epigenetic modifications, phenotypic changes and inflammatory mechanisms of CHIP-related gene mutations, this paper discussed the mechanisms of CHIP-related diseases and possible intervention aimed at aging.

Hematopoyesis Clonal de Potencial Indeterminado (HCPI): más allá de un modelo de campo de cancerización / Clonal hematopoiesis of indeterminate potential (CHIP): Beyond a model of field cancerization

Resumen La Hematopoyesis Clonal de Potencial Indeterminado (HCPI), más conocida como CHIP por sus siglas en inglés, se define como la expansión clonal de Células Madre Hematopoyéticas (CMHs) que albergan una o más mutaciones somáticas (en la mayoría de los casos una sola mutación) sin un cáncer hematológico subyacente ni evidencia morfológica definitiva de displasia, con una frecuencia alélica mayor al 2%. Los individuos con HCPI progresan a malignidad a una tasa de cerca del 0.5% a 1% por año, convirtiéndose así en un modelo de campo de cancerización. Sin embargo, sus implicaciones van más allá debido a que se ha encontrado asociación con enfermedades inflamatorias crónicas, como enfermedad cardiovascular ateroesclerótica, diabetes y enfermedades autoinmunes. Además, es considerado un factor predictivo en pacientes con cáncer hematolológico y no hematológico que reciben quimioterapia y radioterapia.

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) is the expansion of hematopoietic stem cells harboring one or more somatic mutations. These patients do not have underlying hematologic neoplasia, myelodysplasia, or dysplasia, but can progress to a malignant state at a rate of 0.5 to 1% per year. CHIP could be used as a model of field cancerization, since it has been associated with chronic inflammatory diseases, arteriosclerosis, diabetes, and autoimmune conditions. CHIP is also considered a predictive factor in hematological and non-hematological cancer patients receiving chemotherapy and radiotherapy.

Current Aspects of Clonal Hematopoiesis: Implications for Clinical Diagnosis

The broad dissemination of next-generation sequencing capability has increased recognition of clonal hematopoiesis in various clinical settings. In hematologically normal individuals, somatic mutations may occur at an increasing frequency with age in genes that are also commonly mutated in overt myeloid malignancies such as AML and MDS (e.g., DNMT3A, TET2, and ASXL1). This is referred to as clonal hematopoiesis of indeterminate potential (CHIP) and is a benign state; however, it carries a risk of progression to hematologic malignancy as well as mortality primarily because of increased cardiovascular events. In clinical settings, clonal hematopoiesis may be observed in cytopenic patients who do not otherwise meet the criteria for hematologic malignancy, a condition referred to as clonal cytopenias of undetermined significance (CCUS). Distinguishing CCUS from overt MDS or other myeloid neoplasms can be challenging because of the overlapping mutational landscape observed in these conditions. Genetic features that could be diagnostically helpful in making this distinction include the number and biological function of mutated genes as well as the observed variant allele frequency. A working knowledge of clonal hematopoiesis is essential for the diagnosis and clinical management of patients with hematologic conditions. This review describes the key characteristics of clonal hematopoiesis with particular focus on implications for differential diagnosis in patients with CHIP, idiopathic cytopenia, CCUS, and myeloid malignancy.

Progress of clonal hematopoiesis of indeterminate potential / 白血病·淋巴瘤

Clonal hematopoiesis is a common aging_associated biological state. The incidence of malignant neoplasms for the patients with clonal hematopoiesis of indeterminate potential (CHIP) is 0.5%-1% every year. Potential factors of clonal progression in hematopoietic cells have been summarized, including disordered endogenous immunity caused by the augmentation of proliferative pressure, chromosomal instability caused by telomeres short; the amplification of clonal stem cells, acquisition of new mutations, and aging_associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program and epigenetic alterations while failing to support healthy hematopoiesis. CHIP is a vascular risk factor driven by interactions between clonal monocytes_macrophages and the endothelium, as well as a neoplastic progression risk factor driven by the acquisition of additional somatic mutations in the context of many other influences on hematopoiesis and clonal balance. Strategies to reduce the clonal burden associated with CHIP and to inhibit the key inflammatory pathways leading to atherosclerosis could improve the prognosis of the patients.

The clinical significance of gene mutation detection in myelodysplastic syndromes / 天津医药

@#Myelodysplastic syndrome (MDS), a clonal disease that arises from the expansion of mutated hematopoietic stem cells or hematopoietic progenitor cells, is usually characterized by a clinically and biologically heterogeneous group of disorders associated with cytopenias, ineffective hematopoiesis, and a tendency to evolve into acute myeloid leukemia. Currently, the diagnosis of MDS relies mainly on the morphologic and cytogenetic abnormalities. With the advance of the next generation sequencing, genetic mutations have been identified in majority of MDS patients. Here we briefly review the clinical significance of genetic mutations in the diagnosis, classification, risk stratification and treatment of MDS.