Stem cell model of normal and malignant hematopoiesis. Hematopoietic stem cells (HSCs) are capable of self-renewal (semicircular arrow) and reside at the apex of healthy polyclonal hematopoiesis (black). The acquisition of mutations in HSCs (m₁) can create preleukemic HSCs (pHSCs; purple) that can drive clonal hematopoiesis (shaded purple). Clonal evolution through additional mutation acquisition (m_{2, 3, …x}) or other molecular processes can further transform pHSCs into LSCs (red). These LSCs reside at the apex of the AML cellular hierarchy and are capable of (re)generating frank leukemia (brown).