Clonality in context: hematopoietic clones in their marrow environment

Abstract

Clonal hematopoiesis occurs normally, especially with aging, and in the setting of disease, not only in myeloid cancers but in bone marrow failure as well. In cancer, malignant clones are characterized by recurrent somatic mutations in specific sets of genes, but the direct relationship of such mutations to leukemogenesis, when they occur in cells of an apparently healthy older individual or after recovery from immune aplastic anemia, is uncertain. Here we emphasize a view of clonal evolution that stresses natural selection over deterministic ontogeny, and we stress the selective role of the environment of the marrow and organism. Clonal hematopoieses after chemotherapy, in marrow failure, and with aging serve as models. We caution against the overinterpretation of clinical results of genomic testing in the absence of a better understanding of clonal selection and evolution.

Figure 1.

Depictions of Darwinian evolution (after Gould³³). The classic phylogenetic tree (A) entails both adaptation (B) and elimination (C). Emphasis is commonly on the former, ontogeny, as in the display of precursors of current forms of life, with the development of modern man the paragon (D). Natural selection, however, produces many extinct species; the enormous variety and abundance of dinosaur species are underrepresented in the family tree of reptiles, and the diversity of surviving species of this class is limited (E). As Gould emphasized, our focus is on the living end product, not the lost dead ends. A physician’s parents proudly frame the baby picture with stethoscope (F), but most childhood fantasies are not fulfilled and indeed forgotten. These views of evolution apply not only to species and individual organisms but also to diverse cells and cell populations within the bone marrow.

Figure 2.

Clonal hematopoiesis and the environment. The bone marrow contains large numbers of cells (difficult to depict graphically), which by adulthood have stochastically accumulated mutations, most presumably without biological consequence (these cells and clones are shown with variable gray shading). By chance alone, mutations will also occur in genes that do affect function; a cell mutated in the PIGA gene is shown in normal adult bone marrow, because there is experimental evidence that such cells can be isolated from healthy donors. Whether such mutated cells expand to clones is highly dependent on extrinsic conditions. Chemotherapy is the most dramatic example of an environmental perturbation, shrinking (temporarily) the stem and progenitor compartment, effecting genotoxicity, and producing immediate regenerative stress. Selective pressure of the chemotherapy environment favors cells resistant to apoptotic signals, as has been demonstrated for TP53-mutated clones.^,, In immune bone marrow failure, cells not recognized or resistant to immune destruction would be favored: PIGA-mutated cells and cells that have partially lost HLA genes. Additionally, an environment enriched for hematopoietic growth factors and other proliferative signals would allow passive accumulation of cells that normally respond poorly to such stimuli. The aging environment is not yet fully defined, but clonal hematopoiesis likely reflects a diminished stem-cell pool and a lifetime of intermittent inflammation and concurrent diseases, toxic exposures, and many other factors (Figure 3). HSC, hematopoietic stem cell.

Figure 3.

Dynamics of clonal selection. Time and the environment are emphasized in this visualization of hematopoiesis, following the classic diagrams of clonal evolution in myelodysplasia and AML. (A) Cytotoxic chemotherapy produces an acute reduction in hematopoiesis because of strong cell toxicity, in which survival of a cell resistant to apoptotic signals is strongly favored. (B) In immune bone marrow failure, as in AA and hypoplastic MDS, cells resistant to immune attack will be favored, as will cells that thrive in a regenerative environment depleted of normal progenitors but rich in hematopoietic growth factors. (C) Many poorly defined factors likely influence clonal selection with aging. Remarkably, of genes identified as recurrently mutated in myeloid malignancies, limited cassettes are mutated under these environmental stresses: TP53 after chemotherapy; DNMT3A, ASXL1, and BCOR (and PIGA, not a leukemia gene) in aplastic anemia; and TET2, DNMT3A, and ASXL1 in CHIP. HSC, hematopoietic stem cell.