Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

Abstract

Acute myeloid leukemia (AML) has been considered for a long time exclusively driven by critical mutations in hematopoietic stem cells. Recently, the contribution of further players, such as stromal and immune bone marrow (BM) microenvironment components, to AML onset and progression has been pointed out. In particular, mesenchymal stromal cells (MSCs) steadily remodel the leukemic niche, not only favoring leukemic cell growth and development but also tuning their responsiveness to treatments. The list of mechanisms driven by MSCs to promote a leukemia drug-resistant phenotype has progressively expanded. Moreover, the relative proportion and the activation status of immune cells in the BM leukemic microenvironment may vary by influencing their reactivity against leukemic cells. In that, the capacity of the stroma to re-program immune cells, thus promoting and/or hampering therapeutic efficacy, is emerging as a crucial aspect in AML biology, adding an extra layer of complexity. Current treatments for AML have mainly focused on eradicating leukemia cells, with little consideration for the leukemia-damaged BM niche. Increasing evidence on the contribution of stromal and immune cells in response to therapy underscores the need to hold the mutual interplay, which takes place in the BM. A careful dissection of these interactions will help provide novel applications for drugs already under experimentation and open a wide array of opportunities for new drug discovery.

Keywords: bone marrow microenvironment; chemotherapy resistance; hematology; immune microenvironment; mesenchymal stromal cells.

Figure 1

MSC-dependent mechanisms of resistance to therapy. Mesenchymal stromal cells (MSCs) support leukemic cells in diverse ways (purple): (A) supplying pro-survival factors (directly, mediated by extra-vesicle EVs or depending on BM retention), (B) providing metabolic substrates alternative to glucose, (C) rewiring metabolism. Each of these mechanisms interferes with a different therapeutic strategy (red). CKs, cytokines; GFs, growth factors; aa, amino acids; FA, Fatty acids; TNT, tunneling nanotubes; ROS, reactive oxygen species.

Figure 2

Interactions between AML cells and T cells potentially mediate therapy resistance. (A) Intrinsic immune evasion mechanisms adopted by AML cells to escape immune system recognition and destruction (green). These mechanisms include the reduction of AML immunogenicity (e.g., genomic loss of HLA haplotype, downregulation of MHC class II gene expression) and expression of regulatory ligands, such as PD-L1 and Gal-9 on AML cells interacting with their IRs on immune cells (PD-1, TIM-3). (B) AML cell aberrant metabolism, through the expression of metabolic enzymes (e.g., ARG-II and IDO1), leads to glucose deprivation, amino acid starvation, accumulation of kynurenines, etc., affecting T cell functions. (C) The immunologic status of AML patients at diagnosis, including an increased number of Tregs in PB and BM and an exhausted and senescent phenotype of CD8⁺ cells, has been associated with poor prognosis in AML patients. HLA, human leukocyte antigens; MHC, major histocompatibility complex; PD-L1, programmed death-ligand 1; Gal-9, Galectin-9; PD-1, programmed cell death protein 1, TIM-3, T cell immunoglobulin and mucin domain 3; ARG-II, arginase; IDO1, indoleamine 2,3 dioxygenase; ME, microenvironment.

Figure 3

MSC, immune, and leukemic cell mutual interactions. Mesenchymal stromal cells (MSCs) mediate drug resistance through the mechanisms described in Figure 1 (purple). The therapy can influence MSC inflammatory status, modulating MSC immune suppression activity, which leads to suppression of T cell function and induction of Tregs (purple). Immune cell functions are also affected by leukemic cells, which favor an immune-suppressive environment to promote immune escape, through several cell-intrinsic (see Figure 2A,B) and cell-extrinsic mechanisms (i.e., EV release, aberrant metabolism, and the exploitation of other cells through CKs, e.g., IFN-γ which leads to IDO1 upregulation in MSCs) (green). A dysfunctional immune system can also influence the response to therapy (blue) (see Figure 2C). On the contrary, immunotherapy harnesses immune cells to recognize and destroy leukemic cells (blue). At the same time, the activation of the immune system is paralleled by an inflammatory status that could reprogram the MSC behavior, tuning immune suppression (purple). Tregs, T regulatory cells; T eff, T effector cells; EVs, extracellular vesicles; CKs, cytokines; IFN-γ, interferon-γ; IDO1, indoleamine 2,3, dioxygenase 1.