Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications. Significance: Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level. See related article by Menssen et al., p. 330 (31). See related commentary by Romine and van Galen, p. 270. This article is highlighted in the In This Issue feature, p. 265

Cryptococcosis, a fungal disease arising from the etiologic agent Cryptococcus neoformans, sickens a quarter of a million people annually, resulting in over 180,000 deaths. Interestingly, males are affected by cryptococcosis more frequently than females, a phenomenon observed for more than a half century. This disparity is seen in both HIV⁻ (~3M:1F) and HIV⁺ (~8M:2F) populations of cryptococcal patients. In humans, male sex is considered a pre-disposing risk factor for cryptococcosis and males suffering from the disease have more severe symptoms and poorer outcomes. There are numerous observational, clinical and epidemiological studies documenting the male disadvantage in C. neoformans but with no further explanation of cause or mechanism. Despite being commonly acknowledged, little primary research has been conducted elucidating the reasons for these differences. The research that has been conducted, however, suggests sex hormones are a likely cause. Given that the sex difference is both prevalent and accepted by many researchers in the field, it is surprising that more is not known. This review highlights the data regarding differences in sexual dimorphism in C. neoformans infections and suggests future directions to close the research gap in this area.

Supplementary Figure from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Supplementary Table from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Supplementary Figure from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia