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.

Inhibition of CCCTC Binding Factor-Programmed Cell Death Ligand 1 Axis Suppresses Emergence of Chemoresistance Induced by Gastric Cancer-Derived Mesenchymal Stem Cells

“…Recently, increasing evidence has indicated that MSCs become activated during drug treatment and secrete factors that protect tumor cells against a range of chemotherapeutics ( 24 , 25 ). MSCs derived from adipose tissues are involved in a gradual loss of the repair capacity of oxidative DNA damage and accumulation of DNA damage, which are associated with drug resistance ( 26 ).…”

Bone Marrow Aging and the Leukaemia-Induced Senescence of Mesenchymal Stem/Stromal Cells: Exploring Similarities

“…Targeting its CXCR4 receptor (by antagonist or neutralizing antibodies) reduced AML burden and disease progression without affecting HSC engraftment [ 138 ]. Not all of the survival mechanisms induced by MSCs have been totally elucidated, but it is suggested that common adhesion downstream effectors are responsible and may be effective targets of treatment [ 139 ]. AML-derived MSCs showed diminished cell growth and CFU-F, and altered morphology [ 77 , 140 , 141 , 142 ].…”

“…More recently, the role of EVs was also included in the list of mechanisms contributing to AML cells’ protection [ 273 ]. EVs from MSCs and AML cells can reshape the BM microenvironment, and it has been demonstrated that EVs are increased in AML patients’ plasma, even after chemotherapy and remission [ 139 , 274 ]. RNAs, miRNAs and transcripts of FLT3-ITD, nucleophosmin-1 (NPM1), IGF-IR, CXCR4 and MMP9 present within EVs, alter stromal cells, and have important roles in AML treatment and prognosis [ 275 ].…”

In Vitro and In Vivo Modeling of Normal and Leukemic Bone Marrow Niches: Cellular Senescence Contribution to Leukemia Induction and Progression

“…What is known, however, is that the microenvironment characteristics are highly dependent on the dynamics of the niche cell populations (turnover kinetics, physiological state, mutation accumulation rate, among others) [17]. On the other hand, the cross-talk between the niche components implies that an abnormal cell population may also redesign the microenvironment in its favor [14,17,18]; for instance, the experimental evidence highlights the role of non-hematopoietic BM stromal elements in leukemia initiation and progression [19][20][21][22].…”