Somatic mutations and the hierarchy of hematopoiesis

Abstract

Clonal disease is often regarded as almost synonymous with cancer. However, it is becoming increasingly clear that our bodies harbor numerous mutant clones that are not tumors, and mostly give rise to no disease at all. Here we discuss three somatic mutations arising within the hematopoietic system: BCR-ABL, characteristic of chronic myeloid leukemia; mutations of the PIG-A gene, characteristic of paroxysmal nocturnal hemoglobinuria; the V617F mutation in the JAK2 gene, characteristic of myeloproliferative diseases. The population frequencies of these three blood disorders fit well with a hierarchical model of hematopoiesis. The fate of any mutant clone will depend on the target cell and on the fitness advantage, if any, that the mutation confers on the cell. In general, we can expect that only a mutation in a hematopoietic stem cell will give long-term disease; the same mutation taking place in a cell located more downstream may produce just a ripple in the hematopoietic ocean.

BCR–ABL PCR testing in chronic myelogenous leukemia: molecular diagnosis for targeted cancer therapy and monitoring

“…In patients who failed imatinib, ABL kinase domain mutations were more frequently associated with later disease stages, older age and a failure to achieve CCyR by 12 months of therapy; the so-called patients with a 'suboptimal response' [47,48,50,56,57]. Mutations were also more frequently responsible for acquired resistance rather than primary resistance, although the latter has been reported due to duplication of BCR-ABL fusion gene not detectable by Sanger sequencing [58][59][60].…”

“…The detection of ABL kinase domain mutations is also limited by the analytical sensitivity of traditional Sanger sequencing, currently the gold standard platform that can typically detect mutant allele burdens present at~20% (or higher). More importantly, detectable mutations constituting minor clones in periods of low disease burden may not be sufficient justification for a change of management strategy as such clones can often be transient or nonpathogenic [48,[52][53][54][55][56]. Hence, results of mutational analysis must always be interpreted with clinical expertise.…”

The ecology of cancer from an evolutionary game theory perspective

“…Linking haematopoietic stem cells and mature blood cells is often a hierarchically organized process where cells divide and become increasingly differentiated (figure 1). Such a hierarchical tissue architecture has been shown to minimize the impact of most mutations that occur in its cells [13], given the fact that most of them occur in short-lived cell lineages [7]. To capture the dynamics and architecture of haematopoiesis, one needs to consider at least two fundamental processes: cellular reproduction and differentiation [14] (figure 1), processes which are stochastic and coupled [15,16].…”

“…As a result, fitness differences between cell types may arise from mutations that do not change cell reproductive rates: such is the case in chronic myeloid leukaemia (CML), where the fitness of cancer cells relative to that of normal cells can be written in terms of the differentiation rate 1 k of each cell type (figure 1) [7] w cancer w normal…”

Nowe spojrzenie na nocną napadową hemoglobinurię

“…Jeśli do mutacji dochodzi w komórkach na wyższym poziomie rozwoju, na przykład jednostek tworzących kolonie (CFU, colony forming unit), jak ma to miejsce u zdrowych osób i niektórych pacjentów z MDS, to ze względu na brak możliwości samoodtwarzania defektywny klon zanika [7,32,33]. W związku z częstym występowaniem klonu PNH u chorych na AA zaczęto od poszukiwania związku między tymi dwiema chorobami.…”