scholarly journals The Bone Marrow Microenvironment Mechanisms in Acute Myeloid Leukemia

2021 ◽  
Vol 9 ◽  
Author(s):  
Débora Bifano Pimenta ◽  
Vanessa Araujo Varela ◽  
Tarcila Santos Datoguia ◽  
Victória Bulcão Caraciolo ◽  
Gabriel Herculano Lopes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Cellular Mechanisms ◽  
Cytokines And Chemokines ◽  
New Perspective ◽  
Basic Studies ◽  
And Function ◽  
Acute Myeloid

Bone marrow (BM) is a highly complex tissue that provides important regulatory signals to orchestrate hematopoiesis. Resident and transient cells occupy and interact with some well characterized niches to produce molecular and cellular mechanisms that interfere with differentiation, migration, survival, and proliferation in this microenvironment. The acute myeloid leukemia (AML), the most common and severe hematological neoplasm in adults, arises and develop in the BM. The osteoblastic, vascular, and reticular niches provide surface co-receptors, soluble factors, cytokines, and chemokines that mediate important functions on hematopoietic cells and leukemic blasts. There are some evidences of how AML modify the architecture and function of these three BM niches, but it has been still unclear how essential those modifications are to maintain AML development. Basic studies and clinical trials have been suggesting that disturbing specific cells and molecules into the BM niches might be able to impair leukemia competencies. Either through niche-specific molecule inhibition alone or in combination with more traditional drugs, the bone marrow microenvironment is currently considered the potential target for new strategies to treat AML patients. This review describes the cellular and molecular constitution of the BM niches under healthy and AML conditions, presenting this anatomical compartment by a new perspective: as a prospective target for current and next generation therapies.

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.

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

scholarly journals 2559 Role of tissue non-specific alkaline phosphatase (TNAP) in promoting the survival of acute myeloid leukemia (AML) cells within the bone marrow microenvironment

2018 ◽  
Vol 2 (S1) ◽  
pp. 26-27
Author(s):  
Bradley Bowles ◽  
Rosalie M. Sterner ◽  
Kimberly N. Kremer ◽  
Amel Dudakovic ◽  
Jennifer J. Westendorf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Alkaline Phosphatase ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Histone Deacetylase Inhibitors ◽  
Leukemic Cell ◽  
Bone Marrow Microenvironment ◽  
Matrix Mineralization ◽  
Altered Expression ◽  
Acute Myeloid

OBJECTIVES/SPECIFIC AIMS: Treatment of acute myeloid leukemia (AML) is challenging, as apoptosis-resistant AML cells often persist within the bone marrow microenvironment despite chemotherapy. The overall goal of our laboratory is to identify and ultimately target the bone marrow factors that protect AML cells. METHODS/STUDY POPULATION: Using cell cultures, we previously reported that SDF-1 (CXCL12), an abundant bone marrow chemokine, induces apoptosis of isolated CXCR4+ AML cells, including freshly isolated bone marrow-derived AML cells from approximately one-third of AML patients. However, co-culture of AML cells with differentiating osteoblasts protected AML cells from apoptosis. RESULTS/ANTICIPATED RESULTS: Histone deacetylase inhibitors (HDACi) abrogated the ability of osteoblasts to protect AML cells and altered expression of matrix mineralization genes including tissue nonspecific alkaline phosphatase (TNAP). A different drug, cyclosporine A (CSA), similarly inhibited osteoblast-mediated protection of AML cells and reduced TNAP expression. Specifically targeting osteoblast TNAP via siRNA was sufficient to prevent osteoblasts from protecting AML cells in co-cultures. In addition, we are targeting TNAP enzymatically. DISCUSSION/SIGNIFICANCE OF IMPACT: Our results indicate that targeting TNAP may be useful in AML treatment to render the bone marrow microenvironment more hostile to leukemic cell survival.

Acute Myeloid Leukemia Cells Acquire Stem Cell Features in the Bone Marrow Microenvironment

2014 ◽  
Vol 14 ◽  
pp. S119-S120
Author(s):  
V. Lokesh Battula ◽  
Juliana Benito ◽  
Anitha G. Somanchi ◽  
Seshagiri Duvvuri ◽  
Lauren Hodgson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Stem Cell ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Leukemia Cells ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

scholarly journals Role of CYP3A4 in bone marrow microenvironment–mediated protection of FLT3/ITD AML from tyrosine kinase inhibitors

2019 ◽  
Vol 3 (6) ◽  
pp. 908-916 ◽  
Author(s):  
Yu-Ting Chang ◽  
Daniela Hernandez ◽  
Salvador Alonso ◽  
Minling Gao ◽  
Meng Su ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Clinical Activity ◽  
Protective Effects ◽  
Tki Resistance ◽  
Acute Myeloid

Abstract An intriguing aspect of the clinical activity of FMS-like tyrosine kinase 3 inhibitors (FLT3 TKIs) is their apparent higher activity against peripheral blasts from FLT3/internal tandem duplication (ITD) acute myeloid leukemia than marrow disease in the same patients. Accordingly, studies showed that the bone marrow microenvironment plays a role in FLT3 TKI resistance, although the underlying mechanisms are unclear. We recently identified a previously undescribed mechanism by which the bone marrow microenvironment can contribute to drug resistance: expression of cytochrome P450 enzymes (CYPs). In fact, bone marrow stromal cells (BMSCs) expressed most CYPs, including CYP3A4. Because hepatic CYP3A4 plays a role in the inactivation of several FLT3 TKIs, we explored the potential role of CYP3A4 in bone marrow microenvironment–mediated FLT3 TKI resistance. We found that CYP3A4 plays a major role in BMSC-mediated inhibition in the activity of 3 different FLT3 TKIs (sorafenib, quizartinib, and gilteritinib) against FLT3/ITD acute myeloid leukemia (AML). Furthermore, clarithromycin, a clinically active CYP3A4 inhibitor, significantly reversed the protective effects of BMSCs. We show, for the first time, that bone marrow stromal CYP3A4 contributes to FLT3 TKI resistance in the bone marrow. These results suggest that combining FLT3 TKIs with CYP3A4 inhibitors could be a promising strategy toward improving the activity of FLT3 TKIs.

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