scholarly journals Dependence of Acute Myeloid Leukemia on Adhesion within the Bone Marrow Microenvironment

2012 ◽  
Vol 2012 ◽  
pp. 1-4 ◽  
Author(s):  
Pamela S. Becker
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Matrix Proteins ◽  
Growth Inhibitory ◽  
Marrow Stroma ◽  
Resistance To Chemotherapy ◽  
Acute Myeloid

Acute myeloid leukemia (AML) cells home to the endosteal region of the bone marrow. They interact with bone marrow stromal components including extracellular matrix proteins, glycosaminoglycans, and stromal cells, by which they derive proliferative and growth inhibitory signals. Furthermore, adhesion to marrow stroma confers chemotherapy drug resistance and thereby promotes leukemia survival. A subpopulation of the leukemic blasts, known as leukemia stem cells, that are capable of propagating the leukemia, remain sheltered in the bone marrow microenvironment, exhibit resistance to chemotherapy, and serve as the origin of relapse after a variable period of remission. Detachment of these cells from the bone marrow in combination with chemotherapy may improve the outcome of therapy for AML.

scholarly journals The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

2021 ◽  
Vol 22 (13) ◽  
pp. 6857
Author(s):  
Samantha Bruno ◽  
Manuela Mancini ◽  
Sara De Santis ◽  
Cecilia Monaldi ◽  
Michele Cavo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Fate ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Bone Marrow Microenvironment ◽  
Metabolic Adaptation ◽  
Cell Fate Decisions ◽  
Wide Range ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

scholarly journals Leukemia stem cell-bone marrow microenvironment interplay in acute myeloid leukemia development

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Yiyi Yao ◽  
Fenglin Li ◽  
Jiansong Huang ◽  
Jie Jin ◽  
Huafeng Wang
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chemotherapy Resistance ◽  
Bone Marrow Microenvironment ◽  
Cytotoxic Effects ◽  
High Relapse Rate ◽  
Underlying Mechanisms ◽  
Acute Myeloid

AbstractDespite the advances in intensive chemotherapy regimens and targeted therapies, overall survival (OS) of acute myeloid leukemia (AML) remains unfavorable due to inevitable chemotherapy resistance and high relapse rate, which mainly caused by the persistence existence of leukemia stem cells (LSCs). Bone marrow microenvironment (BMM), the home of hematopoiesis, has been considered to play a crucial role in both hematopoiesis and leukemogenesis. When interrupted by the AML cells, a malignant BMM formed and thus provided a refuge for LSCs and protecting them from the cytotoxic effects of chemotherapy. In this review, we summarized the alterations in the bidirectional interplay between hematopoietic cells and BMM in the normal/AML hematopoietic environment, and pointed out the key role of these alterations in pathogenesis and chemotherapy resistance of AML. Finally, we focused on the current potential BMM-targeted strategies together with future prospects and challenges. Accordingly, while further research is necessary to elucidate the underlying mechanisms behind LSC–BMM interaction, targeting the interaction is perceived as a potential therapeutic strategy to eradicate LSCs and ultimately improve the outcome of AML.

Alterations in multipotent mesenchymal stromal cells from the bone marrow of acute myeloid leukemia patients at diagnosis and during treatment

2019 ◽  
Vol 60 (8) ◽  
pp. 2042-2049
Author(s):  
Irina N. Shipounova ◽  
Nataliya A. Petinati ◽  
Alexey E. Bigildeev ◽  
Tamara V. Sorokina ◽  
Larisa A. Kuzmina ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Multipotent Mesenchymal Stromal Cells ◽  
Acute Myeloid

c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia

2015 ◽  
Vol 39 (1) ◽  
pp. 92-99 ◽  
Author(s):  
Bing Xia ◽  
Chen Tian ◽  
Shanqi Guo ◽  
Le Zhang ◽  
Dandan Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Acute Myeloid Leukemia ◽  
Stromal Cells ◽  
Bone Marrow Stromal Cells ◽  
Myeloid Leukemia ◽  
Marrow Stromal Cells ◽  
Acute Myeloid

scholarly journals Acute myeloid leukemia induces protumoral p16INK4a-driven senescence in the bone marrow microenvironment

Blood ◽  
2019 ◽  
Vol 133 (5) ◽  
pp. 446-456 ◽  
Author(s):  
Amina M. Abdul-Aziz ◽  
Yu Sun ◽  
Charlotte Hellmich ◽  
Christopher R. Marlein ◽  
Jayna Mistry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stromal Cells ◽  
Myeloid Leukemia ◽  
Stromal Cell ◽  
Cell Senescence ◽  
Senescent Phenotype ◽  
Age Related ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is an age-related disease that is highly dependent on the bone marrow (BM) microenvironment. With increasing age, tissues accumulate senescent cells, characterized by an irreversible arrest of cell proliferation and the secretion of a set of proinflammatory cytokines, chemokines, and growth factors, collectively known as the senescence-associated secretory phenotype (SASP). Here, we report that AML blasts induce a senescent phenotype in the stromal cells within the BM microenvironment and that the BM stromal cell senescence is driven by p16INK4a expression. The p16INK4a-expressing senescent stromal cells then feed back to promote AML blast survival and proliferation via the SASP. Importantly, selective elimination of p16INK4a+ senescent BM stromal cells in vivo improved the survival of mice with leukemia. Next, we find that the leukemia-driven senescent tumor microenvironment is caused by AML-induced NOX2-derived superoxide. Finally, using the p16-3MR mouse model, we show that by targeting NOX2 we reduced BM stromal cell senescence and consequently reduced AML proliferation. Together, these data identify leukemia-generated NOX2-derived superoxide as a driver of protumoral p16INK4a-dependent senescence in BM stromal cells. Our findings reveal the importance of a senescent microenvironment for the pathophysiology of leukemia. These data now open the door to investigate drugs that specifically target the “benign” senescent cells that surround and support AML.

scholarly journals Human acute myeloid leukemia cells bind to bone marrow stroma via a combination of beta-1 and beta-2 integrin mechanisms

Blood ◽  
1993 ◽  
Vol 82 (10) ◽  
pp. 3125-3132 ◽  
Author(s):  
LJ Bendall ◽  
K Kortlepel ◽  
DJ Gottlieb
Keyword(s):  
Bone Marrow ◽  
Extracellular Matrix ◽  
Acute Myeloid Leukemia ◽  
Cell Adhesion ◽  
Myeloid Leukemia ◽  
Extracellular Matrix Proteins ◽  
Matrix Proteins ◽  
Leukemic Cells ◽  
Beta 2 ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) cells respond to exogenous stimulation from myeloid growth factors that may be secreted by cells of the bone marrow (BM) stroma and retained by glycosaminoglycans in the extracellular matrix. We have analyzed the capacity of malignant cells from patients with AML to maintain close proximity to sites of growth factor production and retention by binding to BM stromal elements, including fibroblasts and extracellular matrix proteins. Leukemic cells from all cases of AML adhered to BM fibroblast (BMF) monolayers (mean +/- standard error [SE] percentage binding, 30.9% +/- 2.5%; n = 23) and to fibronectin and laminin (mean +/- SE percentage binding, 28.0% +/- 4.1% [n = 11] and 21.5% +/- 2.3% [n = 8], respectively). Binding to bovine and human collagen type 1, vitronectin, hyaluronic acid, and albumin was minimal. Analysis of binding mechanisms indicated that very late antigen-4 (VLA-4) and VLA-5 were responsible for AML cell binding to fibronectin. Binding to laminin could be inhibited by antibody to the alpha chain of VLA-6. In contrast, AML cell adhesion to BMF monolayers was not impaired by blocking antibodies to either beta 1 or beta 2 integrins used alone, although the combination of anti-CD11/CD18 and anti-VLA-4 inhibited binding in more than 50% of cases. When anti- VLA-5 was added in these cases, mean +/- SE inhibition of binding of 45.5% +/- 9.1% (P < .001) was observed. Binding of AML cells to extracellular matrix proteins fibronectin and laminin is predominantly beta 1-integrin-dependent, but AML cell adhesion to BMF relies on the simultaneous involvement of beta 1 and beta 2 integrins as well as other currently unrecognized ligands.

Metabolic Reprogramming of Acute Myeloid Leukemia Blasts By Bone Marrow Stroma Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1585-1585
Author(s):  
Dimitrios Mougiakakos ◽  
Regina Jitschin ◽  
Martina Braun ◽  
Andreas Mackensen
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Aerobic Glycolysis ◽  
Treatment Resistance ◽  
Metabolic Phenotype ◽  
Metabolic Shift ◽  
Bone Marrow Stroma ◽  
Marrow Stroma ◽  
Acute Myeloid

Abstract Introduction: Acute myeloid leukemia (AML) represents the most common form of acute leukemia in adults. Despite the enormous efforts during the last decades treatment resistance is still observed at a high rate. Previous studies have shown that bone marrow stroma promotes an increased resilience of AML blasts towards chemotherapeutics. Furthermore, current data suggest that alterations of the malignant cells’ metabolism could represent a strong determinant for the disease’s (including AML) course and/or treatment resistance. In fact, a deregulated metabolism could lead to a reduced sensitivity towards therapy and it remains to be elucidated whether this is a mechanism contributing to the blast-protective effects elicited by the bone marrow stroma. Here, we sought out to characterize the impact of stroma cells on the AML blasts’ metabolism. Methods and Results: The human bone marrow stroma cell-line HS-5 was utilized for establishing the in vitro niche model. We compared in our assays AML cell lines (THP-1, OCI-AML, and KG-1) as well as primary blasts cultured on a HS-5 monolayer or alone. In line with previous observations we could detect an increased proportion of AML cells in the S-phase of the cell cycle upon co-culture with HS-5. When evaluating the cells’ metabolism we observed a shift towards glycolysis despite presence of oxygen, i.e. aerobic glycolysis or the “Warburg”-effect. Basal glycolysis as well as maximal glycolytic capacity upon blocking ATP production in the mitochondrial respiratory chain was increased. Respiration (including basal respiration, coupling efficacy, and maximal respiratory capacity) was not significantly affected. However, mitochondrial biogenesis appeared reduced. Increased glycolysis was accompanied by an increased up-take of fluorescently labeled glucose as well as an increased expression of glucose transporters. The expression of several glycolytic molecules found to be increased upon HS-5 co-culture. Noticeably, cell-to-cell contact was not a pre-requisite for the metabolic shift. Our data was further corroborated by direct observations from AML patients: AML blasts isolated from the bone marrow exhibited an up-regulated glycolysis as compared to their counterparts from the periphery collected at the same time point. Conclusion: Taken together, our data indicates a stromal cell-mediated metabolic shift in AML blasts towards aerobic glycolysis. This metabolic phenotype is linked to an unfavorable prognosis and increased chemo resistance. The underlying molecular pathways remain to be elucidated and could represent a promising target for future interventions. Disclosures No relevant conflicts of interest to declare.

scholarly journals Neuropathy correlated with imbalanced Foxp3/IL-17 in bone marrow microenvironment of patients with acute myeloid leukemia

Oncotarget ◽  
2016 ◽  
Vol 7 (17) ◽  
pp. 24455-24465 ◽  
Author(s):  
Chen Chen ◽  
Yan Liu ◽  
Mingqiang Hua ◽  
Xiaomei Li ◽  
Chunyan Ji ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Acute Myeloid
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