Therapeutic hurdles in acute myeloid leukemia: Leukemic stem cells, inflammation and immune dysfunction

Abstract

Acute myeloid leukemia (AML) is an aggressive and highly heterogeneous hematological malignancy characterized by clonal expansion and differentiation arrest in myeloid progenitor cells. Despite advancements in chemotherapy, allogeneic hematopoietic stem cell transplantation, and post-remission maintenance therapies, the long-term survival remains unsatisfactory with high rates of relapse and refractory. These therapeutic challenges are mediated by multiple factors, including the complexity of the cellular hierarchies in AML, the interaction of leukemic stem cells (LSCs) with the bone marrow niche, inflammation, and immune evasion mechanisms. Further, the absence of specific surface markers that distinguish LSCs from normal hematopoietic stem cells, together with LSCs' functional heterogeneity, complicates targeted treatment approaches. Immune dysfunction, including T cell exhaustion and immune suppression within the bone marrow niche contributes to therapy resistance. In this brief review, we aim to explore current challenges in AML therapy, focusing on LSC-driven resistance, immune evasion, and the need for innovative therapeutic strategies.

Figure 1:. Therapeutic challenges in AML.

Leukemic stem cells (LSCs) possess the ability of self-renewal, initiating tumor development, metabolic rewiring etc. LSCs evade immune response by different mechanisms including promoting dysfunction of immune cells, downregulating antigen presentation to cytotoxic T cells at relapse, cultivating immunosuppressive environment by inflammation etc. Another challenge in AML treatment is lack of surface markers distinguishing LSCfrom normal hematopoietic stem cells (HSC). Surface proteins like CD34, CD123 etc. are generally expressed on both LSC and HSC. The clonal expansion also drives the heterogeneity and selection of resistant leukemic blasts, contributing to therapy resistance and disease relapse.