Myelodysplasia and acute leukemia as late complications of marrow failure: future prospects for leukemia prevention

Abstract

Patients who have acquired and inherited bone marrow failure syndromes are at risk for the development of clonal neoplasms including acute myeloid leukemia, myelodysplastic syndrome, and paroxysmal nocturnal hemoglobinuria. This article reviews the evidence supporting a model of clonal selection, a paradigm that provides a reasonable expectation that these often fatal complications might be prevented in the future.

Figure 1

The fitness landscape for hematopoietic stem cells. A. A popular model of clonal evolution in hematopoietic stem cells proposes that somatic mutations occur stochastically in hematopoietic stem cells and that rare mutations of this kind confer upon the mutant stem cell (red) an inherent proliferative/survival advantage over the non mutant (blue) stem cells. A key principle of this model is that the non mutant stem cells are not unfit, at least at the time the new clone initially evolves. The fitness differences between the evolving clone and the normal stem cell pool can be described as a selection coefficient, here given a value of X. B. An alternative model, one more consistent with studies on clonal evolution in the setting of marrow failure is one in which the entire population of normal hematopoietic stem cells is unfit as a result of environmental stress. A somatic mutant (red) stem cell has developed resistance to the specific environmental stressor so remains fit while the remainder of the stem cell pool has become unfit as a result of environmental stress. In this instance the coefficient for selection of the abnormal clone is identical (X) to that of the model described in A.

Figure 1

The fitness landscape for hematopoietic stem cells. A. A popular model of clonal evolution in hematopoietic stem cells proposes that somatic mutations occur stochastically in hematopoietic stem cells and that rare mutations of this kind confer upon the mutant stem cell (red) an inherent proliferative/survival advantage over the non mutant (blue) stem cells. A key principle of this model is that the non mutant stem cells are not unfit, at least at the time the new clone initially evolves. The fitness differences between the evolving clone and the normal stem cell pool can be described as a selection coefficient, here given a value of X. B. An alternative model, one more consistent with studies on clonal evolution in the setting of marrow failure is one in which the entire population of normal hematopoietic stem cells is unfit as a result of environmental stress. A somatic mutant (red) stem cell has developed resistance to the specific environmental stressor so remains fit while the remainder of the stem cell pool has become unfit as a result of environmental stress. In this instance the coefficient for selection of the abnormal clone is identical (X) to that of the model described in A.

Figure 2

Clonal evolution in acquired aplastic anemia. In the ground state, somatically mutated stem cells do not expand because the mutation doesn’t confer upon that cell a selective advantage. The coefficient of selection for clonal expansion of that cell is low. If the microenvironment remains normal over time (pathway 1), no clonal expansion occurs because the microenvironment is highly supportive of the majority of stem cells in the pool. That is, no clonal evolution occurs in pathway 1 because the relative fitness differences between the normal and mutant cells are trivial. If, however, T-lymphocytes arise that inhibit the replication, expansion or survival of normal hematopoietic stem cells, and if the somatic mutation confers upon a stem cell the capacity to resist the effect of the T cells (by resisting, for example, the apoptotic effects of suppressive cytokines like TNFα and IFNγ), then pathway 2 is most relevant. During the development of aplasia, normal stem cells are suppressed but the mutant one is not and, because the coefficient of selection for that cell is now high (as a result of a decline in fitness of the normal stem cells) it can expand clonally. In some cases the very cytokines that suppress the normal stem cells function to enhance the expansion of the mutant clone. Under continued pressure from the aberrant T cell population, the neoplastic clone preferentially expands over time while the less fit normal HSC are selected against. Not shown in this figure is a theoretical process by which a mutant stem cell arises in a population only after it is exposed to a hostile environment. This would meet strict genetic standards for a truly “adaptive mutation” in which the hostile environment per se induces mutations some of which permit an adaptive response to the environment. In light of the capacity of TNFα to induce oxidative DNA damage, this process is not simply a remote possibility. The coefficient of selection idea would still be relevant here as well because relief of the environmental stress (e.g. fully effective immunotherapy of aplastic anemia) might lower the coefficient in time to prevent an outgrowth of adapted clonal progeny. Finally, in some cases the new clone is able to subordinate the signals from the suppressive population and convert them to growth and survival signals (represented by the dashed line leading from the T-cell in pathway 2). For example, we have noted that in some cases of MDS arising in the context of bone marrow failure, TNFα enhances the proliferation of clonal erythroid and myeloid progenitors, a distinctly aberrant response.

Figure 3

Clonal evolution is adaptive. Fanconi anemia group C mutant cells are intrinsically hypersensitive to the apoptotic effects of TNFα yet clonally evolved cells are resistant., Li et al tested the hypothesis that TNF exposure would change the fitness landscape significantly enough to permit clonal evolution ex vivo. When mutant Fancc stem cells (Kit+, Lin-, Sca1+) were exposed to a combination of hematopoietic growth factors (HGFs) in suspension culture they expanded logarithmically, then, as differentiated cells accumulated cell counts declined. This proliferative capacity of stem cell progeny in vitro was slightly suppressed in Fancc knockout mice, but the slope of the expansion curve did not differ from that of stem cells from wild type mice. However, when the Fancc mutant cells were exposed to both growth factors and TNFα (to which they are intrinsically hypersensitive), there was little expansion at all until late in culture. At this late time point (A) cells that began to proliferate in the face of ongoing TNFα exposure exhibited clonal cytogenetic abnormalities, were TNF resistant, and, when injected into sublethally radiated mice, gave rise to acute myelogenous leukemia.