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Clonal hematopoiesis in the inherited bone marrow failure syndromes.

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Inherited bone marrow failure syndromes (IBMFS) are characterized by ineffective hematopoiesis and increased risk of developing myeloid malignancy. The pathophysiologies of different IBMFS are variable, and can relate to defects… Click to show full abstract

Inherited bone marrow failure syndromes (IBMFS) are characterized by ineffective hematopoiesis and increased risk of developing myeloid malignancy. The pathophysiologies of different IBMFS are variable, and can relate to defects in diverse biological processes, including DNA damage repair (Fanconi anemia), telomere maintenance (dyskeratosis congenita), and ribosome biogenesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome). Somatic mutations leading to clonal hematopoiesis have been described in IBMFS, but the distinct mechanisms by which mutations drive clonal advantage in each disease and their associations with leukemia risk are not well understood. Clinical observations and laboratory models of IBMFS suggest that the germline deficiencies establish a qualitatively impaired functional state at baseline. In this context, somatic alterations can promote clonal hematopoiesis by improving the competitive fitness of specific hematopoietic stem cell clones. Some somatic alterations relieve baseline fitness constraints by normalizing the underlying germline deficit through direct reversion or indirect compensation, while others do so by subverting senescence or tumor suppressor pathways. Clones with normalizing somatic mutations may have limited transformation potential due to retention of functionally intact fitness-sensing and tumor suppressor pathways, while those with mutations that impair cellular elimination may have increased risk of malignant transformation due to subversion of tumor suppressor pathways. Since clonal hematopoiesis is not deterministic of malignant transformation, rational surveillance strategies will thus depend on the ability to prospectively identify specific clones with increased leukemic potential. We describe a framework by which an understanding of the processes that promote clonal hematopoiesis in IBMFS may inform clinical surveillance strategies.

Keywords: hematopoiesis; failure syndromes; clonal hematopoiesis; marrow failure; inherited bone; bone marrow

Journal Title: Blood
Year Published: 2020

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