Fig. 1

Origin of hematological neoplasms from clonal hematopoiesis (a) and TP53-mutated clonal hematopoiesis (b). With age, hematopoietic stem cells (HSCs) acquire somatic mutations and the mutated clones are expanded during HSCs renewal. Early genetic events lead to clonal hematopoiesis (CH) and the origin of clonal hematopoiesis of indeterminate potential (CHIP) or clonal cytopenias of undetermined significance (CCUS), which have different genetic backgrounds, differ in cytopenia status but possess same variant allele frequencies of VAF ≥ 2%. Among these, CCUS have a higher potential of transformation to myelodysplastic syndrome (MDS) with a range of incidence 18–95%. Fitness variants occurring later, confer a growth advantage in the presence of selective pressures such as inflammation, cytotoxic treatment, radiotherapy, bone marrow microenvironment or aging. The consequent selection of high-risk variants, accumulation of the co-occurring mutations, increase in the VAF > 10% and the co-existing cytopenia are predictive of hematopoietic malignancy development and thus, accelerate the progression to hematological neoplasm; myelodysplastic syndrome (MDS) and MDS/AML. TP53-mutated CH occurs in about 2–6% of cancer patients. TP53-mutated MDS and AML account for up to 13% of all de novo cases. In therapy-related myeloid neoplasm, TP53 gene mutations are present in 20–40% of cases [5]. The model shows the pathogenesis of MDS and AML in hereditary cancer syndromes; Li-Fraumeni syndrome (LFS) with congenital TP53 mutations and Schwachman syndrome (SDS) with congenital mutations in Schwachman–Bodian–Diamond syndrome (SBDS) gene and in therapy-related myeloid neoplasm (t-MN); diseases in which TP53 monoallelic mutations play a role in the progression from CH to myeloid malignancy. The incidence of malignant transformation is higher in the presence of selective pressure as delineated for SDS and t-MN. →  →  → tandem of arrows indicates a multi-step process. Modified from [1, 6, 7]. Created with BioRender.com