Unraveling complex karyotype clonal architecture: co-existing double TP53 mutations alongside DNMT3A, TET2, and NF1 mutations - a case study.

Complex chromosomal changes in Acute Myeloid Leukemia (AML) are highly heterogeneous, with disease progression shaped by both the number and nature of abnormalities. Rarely do, multiple unrelated clones with independent chromosomal changes coexist at diagnosis. Present study showcases a comprehensive characterization of two cytogenetically distinct complex clones in AML, driven by non-cyclic and chromoplexy mechanisms, highlighting their co-existence with key molecular alterations (TP53, NF1, DNMT3A, TET2) along with their potential contribution to clonal evolution. In the present study a refined assessment of clonal chromosomal complexity is provided, with each clone exhibiting distinct alterations involving chromosomes 5, 14, and 17 along with variant structural formation of chromosomes ie. isochromosome 5p, partial monosomy 7 and derivative 17, defining the heterogeneity of clonal architecture. Additionally, we propose a probable association between mutational burden and chromosomal complexity, as evidenced by the coexistence of distinct clones with varying mutation loads and cytogenetic profiles, reflecting parallel clonal evolution. Our integrated approach combining karyotyping and fluorescence in situ hybridization (FISH) was essential in unraveling the clonal architecture, providing valuable insights into the personalized chromosomal alterations and pathogenetic mechanisms that would be helpful for refining prognosis and guiding AML management.