Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL)

Abstract

Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance. Considering the diversity of organs infiltrated by T-ALL cells and the unique cellular components of the microenvironment encountered at each site, it is likely that there are both shared features of tumor-supportive niches across multiple organs and site-specific features that are key to leukemia cell survival. Therefore, elucidating the distinct microenvironmental cues supporting T-ALL in different anatomic locations could reveal novel therapeutic targets to improve therapies. This review summarizes the current understanding of the intricate interplay between leukemia cells and the diverse cells they encounter within their tumor microenvironments (TMEs), as well as opportunities to therapeutically target the leukemic microenvironment. T-cell Acute lymphoblastic leukemia (T-ALL) is an aggressive, predominantly pediatric, cancer arising from excessive proliferation of transformed immature T cells in the thymus. Despite treatment advancements, patients experience significant side effects of chemotherapy, and those who fail to respond or relapse face poor outcomes, highlighting the need for more effective treatment strategies. This review examines how the tumor microenvironment supports growth and survival of T-ALL cells. The authors discuss current evidence indicating that interactions between T-ALL cells and the TME contribute to disease progression and treatment resistance in various organs, including the bone marrow, central nervous system, and spleen. These studies suggest that targeting interactions between T-ALL cells and the TME could offer new treatment opportunities. The authors conclude that disrupting the supportive signals of the TME could enhance existing therapies and reduce disease relapse. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.