Acute myeloid leukemia (AML) is a highly heterogeneous and aggressive hematological malignancy characterized by the arrested differentiation and clonal expansion of immature myeloid cells. Despite advances in induction chemotherapy, post-remission consolidative therapies, and allogeneic hematopoietic stem cell transplantation (HSCT), the 5-year survival rate remains as low as ∼30%, with high rates of relapse and refractory disease1, 2. This therapeutic challenge largely traces back to AML’s hierarchical complexity, particularly the persistence of minimal residual disease (MRD) attributed to leukemic stem cells (LSCs) which possess self-renewal capabilities and are thought to be key in disease initiation, maintenance, and relapse3, 4. The LSC concept originated from Lapidot et al.[5], who showed that a small proportion of leukemic cells characterized by CD34+CD38- expression, give rise to leukemia in immunodeficient mice. Dick and colleagues[6] later revealed that AML cells are organized in a hierarchical manner, with LSCs residing at the apex forming downstream differentiated states. Indeed, LSCs are resistant to conventional induction chemotherapy, serving as a reservoir for relapsed disease[7]. To add more complexity, LSCs can be regulated in a bidirectional way, allowing them to produce more differentiated leukemic cells or revert to the immature state by PU.1 suppression[8]. This flexibility contributes to a complex hierarchical organization of AML and underpins its therapy resistance as different cellular states can acquire distinct mechanisms of resistance.

However, distinctive markers that target LSCs while sparing other cells, or that are homogenously expressed on AML cells remain lacking. For instance, higher expression of CD44[9], CD96[10] or CD123[11] is reported in LSCs compared to normal compartments, providing potential targets for immunotherapy to eradicate LSCs. However, these markers are also expressed on normal tissues, or are not expressed in all AML cells, leading to either unacceptable toxicity, or incomplete eradication of the disease, respectively. Thus, other mechanisms of therapeutic resistance that may be targetable have been explored. For example, immune dysfunction12, 13. ∗, 14 and immune escape of LSCs15, 16, 17 coupled with an inflammatory microenvironment18, 19. ∗∗, 20 are increasingly being recognized as contributors to therapeutic resistance. The AML niche also allows for crosstalk between blasts, stroma, and immune cells driving an immunosuppressive microenvironment to escape immune surveillance and suppress immune responses[21]. This review aims to discuss the different roles of these factors in contributing to AML therapeutics resistance (Figure 1).