Jesús Pérez‐Losada

BCR-ABL is a chimeric oncogene generated by translocation of sequences from the chromosomal counterpart (c-ABLgene) on chromosome 9 into the BCR gene on chromosome 22. Alternative chimeric proteins, BCR-ABLp190 and BCR-ABLp210, are produced that are characteristic of chronic myelogenous leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph1-ALL). In CML, the transformation occurs at the level of pluripotent stem cells. However, Ph1-ALL is thought to affect progenitor cells with lymphoid differentiation. Here we demonstrate that the cell capable of initiating human Ph1-ALL in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID), termed SCID leukemia–initiating cell (SL-IC), possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all Ph1-ALL analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34+CD38−, which is similar to the cell-surface phenotype of normal SCID-repopulating cells. This indicates that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation in Ph1-ALL.

Cutaneous squamous cell carcinoma (CSCC) is the second most frequent cancer in humans and its incidence continues to rise. Although CSCC usually display a benign clinical behavior, it can be both locally invasive and metastatic. The signaling pathways involved in CSCC development have given rise to targetable molecules in recent decades. In addition, the high mutational burden and increased risk of CSCC in patients under immunosuppression were part of the rationale for developing the immunotherapy for CSCC that has changed the therapeutic landscape. This review focuses on the molecular basis of CSCC and the current biology-based approaches of targeted therapies and immune checkpoint inhibitors. Another purpose of this review is to explore the landscape of drugs that may induce or contribute to the development of CSCC. Beginning with the pathogenetic basis of these drug-induced CSCCs, we move on to consider potential therapeutic opportunities for overcoming this adverse effect.

The stem cell factor c-kit signaling pathway (SCF/c-kit) has been previously implicated in normal hematopoiesis, melanogenesis, and gametogenesis through the formation and migration of c-kit(+) cells. These biologic functions are also determinants in epithelial-mesenchymal transitions during embryonic development governed by the Snail family of transcription factors. Here we show that the activation of c-kit by SCF specifically induces the expression of Slug, a Snail family member. Slug mutant mice have a cell-intrinsic defect with pigment deficiency, gonadal defect, and impairment of hematopoiesis. Kit(+) cells derived from Slug mutant mice exhibit migratory defects similar to those of c-kit(+) cells derived from SCF and c-kit mutant mice. Endogenous Slug is expressed in migratory c-kit(+) cells purified from control mice but is not present in c-kit(+) cells derived from SCF mutant mice or in bone marrow cells from W/W(v) mice, though Slug is present in spleen c-kit(+) cells of W/W(v) (mutants expressing c-kit with reduced surface expression and activity). SCF-induced migration was affected in primary c-kit(+) cells purified from Slug-/- mice, providing evidence for a role of Slug in the acquisition of c-kit(+) cells with ability to migrate. Slug may thus be considered a molecular target that contributes to the biologic specificity to the SCF/c-kit signaling pathway, opening up new avenues for stem cell mobilization.