From bone marrow failure syndromes to VEXAS: Disentangling clonal hematopoiesis, immune system, and molecular drivers

Clonal hematopoiesis (CH) is a result of the selective expansion of hematopoietic stem and progenitor cells (HSPCs) carrying somatic mutations originating from a primary HSC. The advent of modern genomic technologies has helped recognizing that CH is common in elderly healthy subjects as a result of the aging bone marrow (BM). CH in healthy subjects without abnormalities in blood counts is known as CH of indeterminate potential. CH is also seen in BM failure (BMF) disorders. Whether CH alarms for the risk to develop malignant evolution in BMF or creates an adaptation to selective pressure is a matter of controversy. As such, a continuum might exist from pre-malignant to malignant hematopoietic diseases. This review summarizes how somatic mutations and immune derangement in HSCs shape disease evolution and describes the complexity of disorders such as VEXAS as the prototypic tetrad of somatic mutations, morphologic features, inflammatory pathways and immune overshooting. In such a view, we interconnect the axis aging and immune-hematopoietic system, which all convey important clues for the risk to develop malignancies.