Hema-seq reveals genomic aberrations in a rare simultaneous occurrence of hematological malignancies

The co-occurrence of multiple myeloma and acute myelogenous leukemia is an extremely rare phenomenon, with only a few cases reported globally. These two neoplastic cells commonly originate from a multipotent hematopoietic stem cell, but depending on clonal acquisition or loss at a lower level, they diverge from each other. In this study, we aimed to identify clonal changes in heterogeneous hematopoietic lineages by integrating whole-genome sequencing, copy number variations, cell morphology, and cytogenetic aberrations at the single-cell level. To achieve this, we selected corresponding cells from Wright-stained slides and performed whole-genome sequencing using the novel Hema-seq technique. We also selected cytogenetically aberrant and normal cells at the single-cell level from slides stained with fluorescent probes and performed whole-genome sequencing using the Hema-seq technique. This study represents the first success in using WGS to select single cells depending on cytogenetic changes. By integrating the results from each cell lineage, we inferred sequential clonal changes along the hematopoietic tree, revealing the decisive changes leading to the myeloma cell and AML cell. Our findings demonstrate the power of Hema-seq in resolving genomic heterogeneity in rare, complex hematological malignancies, shedding light on clonal evolution and potential therapeutic targets for these diseases.