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.

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.

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.

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.