Models for the expansion of hematopoietic clones and the progression of into a hematologic cancer. (A) Expansion of a hematopoietic stem cell into a clonal population under the influence of a driver somatic mutation conferring a growth advantage to the cell, and potential progression into a myeloid neoplasm through the acquisition of subsequent subclonal driver mutations. (B) Expansion of a hematopoietic malignant clone under the influence of a driver mutation inferred from sequencing analysis and an undetected or as-yet-unknown cooperating mutation. In this scenario, the expected time to progression of the malignant clone to a clinical stage would be significantly shorter than under condition outlined in panel A. (C) Selection of a hematopoietic stem cell carrying a somatic mutation under the pressure of bone marrow environmental changes. The mutated clone is more fit to survive in an abnormal microenvironment than normal stem cells, and may expand sustaining a clonal hematopoiesis and eventually progress through the acquisition of subsequent subclonal driver mutations.