Introduction: Acral lentiginous melanoma (ALM), a rare subtype, accounts for 2–3% of melanoma cases, primarily affecting the palms, soles, and nail beds and disproportionately affects people of color. This review focuses on clinical insights into ALM and its management, with a focus on race and ethnicity. Methods: A comprehensive literature search was conducted in public databases using the search term “acral melanoma,” and studies focusing on epidemiology, clinical presentation, and treatment outcomes of ALM in various racial and ethnic groups were reviewed. Results: Significant disparities in ALM outcomes exist across racial and ethnic groups, with African, Hispanic, and Asian individuals presenting with thicker, more advanced tumors at diagnosis. These populations encounter unique challenges, including limited access to dermatologic care, under-recognition of melanoma presentation in darker skin types, and socioeconomic barriers leading to delayed diagnosis and treatment. Surgical management may require specialized approaches, such as partial amputation for subungual melanomas. Additionally, there is uncertainty regarding the tumor immune microenvironment (TME) in ALM, with some studies suggesting that it might be less favorable, resulting in a lower response to immunotherapy. Conclusions: ALM affects diverse populations, and the impact of ethnic and racial origin on ALM biology is largely unknown. Addressing disparities in ALM outcomes among racial and ethnic groups is critical for improving patient care. Increased awareness of melanoma risk in individuals with darker skin can significantly impact early detection and treatment. Future research should focus on the genetic and biological factors contributing to morbidity and mortality in ALM patients.

In the published publication [...].

Summary: The fate choice between stem cell self-renewal and differentiation is regulated by bistable transcriptional networks, which are balanced in homeostasis and imbalanced in tumors. Yet, how stem cells switch from self-renewal to differentiation remains a conundrum. Here, we discover a molecular mechanism that allows stem cell-like tumor propagating cells (TPCs) in squamous cell carcinomas (SCCs) to switch from a mutually exclusive SOX2-PITX1-TP63 self-renewal circuit to a KLF4 driven differentiation program, dependent on the relative occupancy of a novel Klf4 -regulatory enhancer cluster ( Klf4 ^EC944 ) by SOX2 or KLF4, respectively. We find SOX2 occupies this site in TPCs to inhibit Klf4 transcription, but upon phosphorylation SOX2 becomes evicted from Klf4 ^EC944 , allowing residual KLF4 to occupy this site instead, boost the expression of KLF4 and its downstream targets, and differentiate self-renewing TPCs into post-mitotic SCC cells. This mechanism allows SOX2 to promote self-renewal and tumor formation, while preserving the differentiation potential in SCC cells. Our data suggest that stochastic cell fate decisions depend on the effective concentration of enzymatically regulated transcription factors. The surprising specificity by which SOX2-phosphorylation governs the bistable Klf4 ^EC944 network-switch in SCCs reveals a conceptual framework for the identification of similar switches in other stem cell and cancer types and their potential development into cell type specific differentiation therapies for diseases in which tissue homeostasis has gone awry.