Leukemic stem cell signatures in Acute myeloid leukemia- targeting the Guardians with novel approaches.

Abstract

Acute myeloid leukemia is an aggressive hematopoietic stem cell malignancy with poor outcomes despite the available treatment options including standard chemotherapy, selective targeted therapy and stem cell transplantation. Approximately ~30-40% of AML patients are refractory to initial therapy or succumb to relapse. Induction failure result from inherent resistance to chemotherapy, which is primarily driven by the chemo-resistant residual leukemic stem cells (LSC) that lead to disease progression and recurrence. The rarity and lack of universal surface markers for the identification and isolation of AML LSC renders a major challenge. Therefore, a perpetual quest for novel markers to characterize LSC and design anti-LSC therapies is ongoing. The evolving technologies from high-throughput bulk cell sequencing to high-dimensional single cell analysis has begun to decode the cellular hierarchies and dysregulated transcriptional networks in AML. These inherent properties of LSC as well as cross-talk with the extrinsic bone marrow microenvironmental milieu induce a conducive environment for leukemogenesis by secretion of various cytokines, chemokines and growth factors that shield LSC against conventional chemotherapy. To overcome these barriers, novel approaches of intratumoural delivery that focus on immune-mediated eradication by inducing microenvironmental changes within the tumour as well as avoid systemic toxicity seem encouraging. Selective targeting of LSC and their protective bone marrow niche holds immense potential as a promising therapeutic strategy for AML. Novel multimodal anti-LSC therapies are being explored that can overcome chemo-resistance and immune escape combined with reduced toxicity and sustained delivery may improve remission and survival rates in AML patients and decrease relapse.