Emerging clonal complexity has brought into question the way in which we perceive and, in turn, treat disorders of the hematopoietic system. Former models of cell-intrinsic clonal dominance driven by acquisition of driver genes in a stereotypic sequence are often insufficient in explaining observations such as clonal hematopoiesis, and new paradigms are in order. Here, we review the evidence within the hematologic malignancy field and also borrow from perspectives rooted in evolutionary biology to reframe pathogenesis of hematologic disorders as dynamic processes involving complex interplays of genetic and nongenetic subclones and the tissue microenvironment in which they reside. SIGNIFICANCE: Hematopoietic malignant and premalignant syndromes exhibit vast clonal diversity that is subject to selection imposed by the tissue microenvironment, as well as artificial selection by therapy. Tackling these disorders requires an appreciation of heterogeneity at both genetic and nongenetic levels, which can be borrowed from evolutionary biology principles. Models and drug development strategies that veer away from targeting solely dominant clones and, instead, embrace this complexity to outsmart it are required for long-term remission.
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