Extrinsic factors contributing to leukemic progression. Germ line mutations in GATA2 or SAMD9/9L may contribute to a reduction in the clonal complexity of the hematopoietic system, providing the impetus for rapid expansion of mutant clones derived from an inflamed, oft-challenged, and hypocellular adolescence bone marrow microenvironment (blue). TAM originates in the fetal liver after the acquisition of GATA1 mutations in trisomy 21 progenitors and migrates to the pediatric bone marrow, in which IFN hyperactivity and inflammation may drive the acquisition of further leukemic mutations (yellow). CH/CCUS/MDS progression is influenced by an aging hematopoietic niche, chronic inflammation, and myeloid skewing of mutant clones (red). ATXPC, ataxia pancytopenia. Figure created with Biorender.com.