Normal and Leukemic Hematopoietic Stem Cells and Lineages

Abstract

The spleen colony assay in which single cells injected into heavily irradiated mice produce colonies (clones) that contain cells representing all three myelopoietic lineages (plurpiotent), developed by the author and J. E. Till, was a milestone in the study of hematopoietic stem cells (HSCs) and lineages. Hematopoietic development requires interaction of stem cell factor with its receptor c-kit on stem cells. A hierarchy of stem and progenitor cells results in different lines of differentiaton by transit-amplifying cells belonging to different sublineages and responding to different growth factors. A more primitive stem cell than the spleen colony-forming cell was identified by cell sorting, and a set of cell markers may now be used to identify cells at different stages of the hematopoietic lineage. Bone marrow transplantation studies show that HSCs can give progeny that contribute to other organs, such as liver, muscle, and brain, and “stem” cells from other tissues, such as muscle and brain can produce blood precursor cells. Malignancies of the hematopoietic system are manifested by either an increased growth fraction (acute leukemias) or decreased death fraction (maturation arrest and failure of cells to die). In very simplistic terms, cure of acute leukemia requires elimination of the most primitive stem cell, which harbors the genetic change; cure of chronic leukemias requires ways to force cells to differentiate and die.