AML subclones can correspond to distinct cell populations with different functional capacities.
Major finding: AML subclones can correspond to distinct cell populations with different functional capacities.
Concept: Rare subclones can preferentially engraft in immunodeficient mice and skew the clonal architecture.
Impact: Tumors should be genomically characterized before and after xenotransplantation.
Intratumoral heterogeneity arises during tumor evolution as subpopulations of cells acquire additional mutations that were not present in the initial founding clone. Functional heterogeneity can also exist among primary tumor cells, but the relationship between functional heterogeneity and clonal organization within tumors is unclear. Klco and colleagues performed whole-genome sequencing of bone marrow cells from 19 patients with de novo acute myeloid leukemia (AML) and identified founding clones and leukemic subclones based on the variant allele fraction of somatic mutations. All subclones were present in corresponding peripheral blood samples, suggesting that different AML subclones have an equal propensity to peripheralize. However, some AML subclones corresponded to morphologically distinct leukemic cell populations, such as monocytes or blasts, indicating that subclones can differ in their capacity for differentiation. Some AML subclones also had different growth properties, with some primary AML samples retaining their original clonal organization after being cultured on stromal cells, and others showing substantial enrichment of individual subclones. Consistent with these findings, sequencing of patient-derived AML bone marrow xenografts showed preferential engraftment of individual subclones, many of which were only minor subclones in the primary AML sample and were not predominant in patients at relapse. In some cases, subclone engraftment was dependent on the mouse strain used, and the immunophenotype of the predominant subclone could be affected by the cytokine milieu of the host. Importantly, this preferential engraftment led to significant subclonal restriction, with many xenografts composed of only a single subclone and none maintaining the exact clonal organization as the primary AMLs from which they were derived. In addition to demonstrating that tumor subclones arising from the same founding clone can be phenotypically and functionally heterogeneous, these findings caution against generalizing experimental data obtained from xenografts to parental tumors without performing genomic analyses before and after xenotransplantation.
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