الفهرس 
Introduction & aim of the workOnly 14 pages are availabe for public view
 |  | from | 139 |  |  |
| | | from | 139 | | |
Abstract
Clonal mutations in genes that are recurrently mutated in hematologic malignancies are commonly detected in the blood of otherwise healthy aging people.
While model systems affirm a self- renewal advantage for HSCs with DNMT3A and TET2 mutations, the mechanisms of clonal expansion are poorly understood for these and most other CHIP mutations. It also remains to be seen how niche dynamics interact with somatically mutated HSCs. While clonal advantage may be due to altered balance of self-renewal versus differentiation, competition for limited trophic signals, as seen in germinal center B cells, is another potential basis for the competitive advantage of mutant cells. Detection of CHIP in routine clinical practice has implications for both refined risk assessment and, potentially, for interventions that modify disease risk. If clones can be therapeutically suppressed, the role for broad screening for CHIP may become unequivocal.
Members of several groups have described two ‘pre-malignant’ myeloid conditions, namely idiopathic cytopenia of undetermined significance (ICUS) and idiopathic bone marrow dysplasia of uncertain significance (IDUS). Both conditions may progress to an overt myelodysplastic syndrome (MDS), but may also progress to another myeloid neoplasm such as acute myeloid leukemia, a myeloproliferative neoplasm (MPN), or a mast cell disorder (mastocytosis). In ICUS the dysplasia is mild and does not fulfill the WHO criteria for MDS but cytopenias can be severe. In IDUS the dysplasia is prominent but cytopenias, if detectable, are mild. In both conditions it is possible that a neoplastic clone has already replaced most or all of normal bone marrow cells when ICUS or IDUS is detected, but evidence to support this possibility is not necessarily available.
Improved understanding of hematopoiesis in aging persons requires revisiting the boundary between health and disease and re-examination of what specific alterations are necessary to label a patient as having MDS. Clonal hematopoiesis in the absence of cytopenias is of indeterminate potential, but conveys health risks, and is likely to become more common as the global population ages. In the future, detection of an initiating mutation might prompt interventions to eliminate a developing dangerous clone and restore normal hematopoiesis, opening up a new field of preventive hematology applicable to CHIP, as well as MGUS, MBL, and other clonal preneoplastic conditions.
Future perspectives
Chronic unexplained mild cytopenias are a challenge in clinical practice. In many cases, no underlying cause is detected even after extensive evaluations, including BM investigations. In these patients, the diagnosis of ICUS is appropriate. In other patients, an underlying nonhematologic or hematologic disease, often in the form of an MDS, is detected after extensive investigations or in the follow-up period. Especially in elderly patients, an overt MDS may develop after a variable latency period. Although no parameter is specific for any cause of cytopenia in these patients, the numbers of CFU progenitor cells and flow cytometric studies may yield additional information useful for the delineation of MDS and other BM disorders from nonhematologic causes of cytopenia.