scholarly journals Far from Health: The Bone Marrow Microenvironment in AML, A Leukemia Supportive Shelter

Children ◽  
2021 ◽  
Vol 8 (5) ◽  
pp. 371
Author(s):  
Stephanie Sendker ◽  
Katharina Waack ◽  
Dirk Reinhardt
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment ◽  
Leukemic Cells ◽  
Therapeutic Approaches ◽  
Complex Interplay ◽  
Comprehensive Overview ◽  
Future Challenges ◽  
Cellular Components

Acute myeloid leukemia (AML) is the second most common leukemia among children. Although significant progress in AML therapy has been achieved, treatment failure is still associated with poor prognosis, emphasizing the need for novel, innovative therapeutic approaches. To address this major obstacle, extensive knowledge about leukemogenesis and the complex interplay between leukemic cells and their microenvironment is required. The tremendous role of this bone marrow microenvironment in providing a supportive and protective shelter for leukemic cells, leading to disease development, progression, and relapse, has been emphasized by recent research. It has been revealed that the interplay between leukemic cells and surrounding cellular as well as non-cellular components is critical in the process of leukemogenesis. In this review, we provide a comprehensive overview of recently gained knowledge about the importance of the microenvironment in AML whilst focusing on promising future therapeutic targets. In this context, we describe ongoing clinical trials and future challenges for the development of targeted therapies for AML.

Novel Cryptic Collagen IV Mediated Activation of Discoidin Domain Receptor 1 (DDR1) in Bone Marrow Microenvironment May Promote Migration in Myeloid Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2429-2429
Author(s):  
Amanda J Favreau ◽  
Peter C Brooks ◽  
Pradeep Sathyanarayana
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Collagen Iv ◽  
Bone Marrow Microenvironment ◽  
Leukemic Cells ◽  
Migration Rates ◽  
Native Collagen ◽  
First Time ◽  
Discoidin Domain Receptor 1

Abstract Abstract 2429 Acute myeloid leukemia (AML) represents a heterogeneous group of malignancies with huge variability in clinical course and response to therapy. Discovery of new prognostic factors in AML is enhancing our understanding of disease biology and helping to identify new therapeutic targets. Previously, we showed for the first time that Discoidin Domain Receptor 1 (DDR1), a class of collagen-activated receptor tyrosine kinase, was highly expressed on bone marrow derived CD33+ leukemic blasts of AML patients, however, its functional role was not known. Here in, we attempt to understand the role of the bone marrow microenvironment in promoting DDR1 activation and its subsequent functional role in migration of leukemic cells. Initial screening of several leukemic cell lines for DDR1 expression identified K562 as an optimal system for further studies due to high DDR1 expression. In addition to native collagen IV, the current studies also tested for the first time the ability of the cryptic collagen IV in activation of DDR1. Proteolytic remodeling of the collagenous extracellular matrix (ECM) have been shown to result in generation of cryptic collagen epitopes, which under normal physiologic conditions, are masked in its 3-dimensional structure. Previously, the functional cryptic site of collagen IV was shown to be highly expressed within the extracellular matrix (ECM) of malignant tumors and within the sub-endothelial basement membrane of tumor-associated blood vessels. Presently, exposure of K562 cells to denatured collagen IV resulted in statistically significant (p<0.045) migration rates compared to native collagen IV. Further, exposure of denatured collagen IV lead to increased activation of DDR1 in comparison to native collagen IV as assessed via phosphorylation of DDR1 at activation sites of Y792, Y796 and Y797 respectively using phospho-DDR1 sandwich ELISA approach. Importantly, co-incubation with HU-IV 26, a previously characterized monoclonal antibody against cryptic collagen IV epitope significantly (p<0.0003) decreased the phospho-DDR1 levels. Interestingly co-incubation with HU-IV 26 did not significantly alter the migration rates between native and denatured collagen IV. To test the role of matrix metalloproteinases (MMPs) in DDR1 induced migration, MMP2 and MMP9 levels were assayed via zymogram and western blots using conditioned media to assess levels of secreted MMPs. Overall, active and inactive MMP-2 levels were higher when exposed to native or denatured collagen IV compared to serum-free only culture conditions. Currently these outcomes suggest a possible feed forward loop for collagen IV-DDR1-MMP2-cryptic collagen IV in promoting migration of leukemic cells. We next examined the levels of collagen IV and cryptic collagen IV in bone marrow derived leukemic blasts of AML patients (n=24) using HU-IV 26 and a native collagen IV antibody via generating a tissue microarray (TMA) and performing immunohistochemistry (IHC). In comparison to control samples (n=9), native collagen and cryptic collagen IV levels were found in significantly high levels (p<0.019 & p<0.034 respectively). Most importantly, the levels of cryptic collagen IV were significantly higher than native collagen (p<0.05) in AML patients. Significantly, the DDR1 levels were concurrently elevated in the same AML patients with high cryptic collagen IV as examined via TMA and IHC. Taken together, for the first time we demonstrate that cryptic collagen IV is a potent activator of DDR1 and high levels of cryptic collagen IV is expressed in leukemic cells of AML patients. Further understanding of this phenomenon may lead to the development of therapeutic agents that directly modulate the bone marrow microenvironment and attenuate leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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.

Novel Role of HDAC Inhibitors in Bone Marrow Microenvironment: Activation of Leukemia Cell Phagocytosis through Annexin A1.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2219-2219
Author(s):  
Yoko Tabe ◽  
Rooha Contractor ◽  
Susanne Radke ◽  
Michael Andreeff ◽  
Marina Konopleva
Keyword(s):  
Bone Marrow ◽  
Membrane Binding ◽  
Hdac Inhibitors ◽  
Leukemia Cell ◽  
Cdna Array ◽  
Bone Marrow Microenvironment ◽  
Leukemic Cells ◽  
Annexin A1 ◽  
Induced Apoptosis

Abstract Annexin A1 (ANX-A1) is a calcium-dependent membrane-binding protein involved in the modulation of apoptosis and phagocytosis (FASEB J.2003;17:1544). We have previously reported that HDAC inhibitor depsipeptide (FK228) caused marked growth inhibition and apoptosis in t(8;21) Kasumi-1 AML cells with up-regulation of 123 genes (by cDNA array) including ANX-A1 (3.5 fold; Tabe, Blood 2004). By chromatin immunoprecipitation (ChIP) assay, FK228 induced H4 and H3-K9 acetylation in the ANX-A1 promoter with corresponding induction of ANX-A1 mRNA (7.2±1.7 fold, TaqMan RT-PCR) and protein (western blot analysis). The markedly increased ANX-A1 protein localized on the cell membrane of Kasumi-1 cells exposed to FK228 was confirmed by immunofluorecence analysis using confocal microscopy. ANX-A1 membrane localization was diminished by treatment with anti-ANX-A1 mAb. To investigate the contribution of ANX-A1 to FK228-induced apoptosis, we neutralized ANX-A1 by anti-ANX-A1 mAb. This moderately decreased FK228 induced apoptosis (36.0±4.1 vs 26.5±3.7% AnnexinV(+)/PI(+) cells, p=0.01). Similarly, Kasumi-1 cells transfected with siRNA/ANX-A1 were less sensitive to FK228-induced cell death compared with nonsense (N) siRNA transfected cells (siRNA 31.2±3.1% vs NsiRNA 39.5±2.9% annexin(+) cells, p=0.03). These data indicate that the upregulation of endogeneous ANX-A1 (either membrane-binding or secreted form) promotes cell apoptosis in an autocrine fashion. Next, we investigated the functional role of ANX-A1 on leukemia cell phagocytosis. The engulfment of Kasumi-1 cells by cocultured human THP-1 monocyte-derived macrophages was evaluated by cell adherence assay. Compared with untreated cells, the exposure to FK228 induced a dramatic increase in Kasumi-1 cells attachment to macrophages (untreated vs FK228 treated; 57 ± 9 cells vs 196 ± 33 cells/ microscopic fields (0.08 mm2/field), n = 5; p=0.01). FK228-induced cell attachment was completely abrogated in the siRNA/ANX-A1 transfected Kasumi-1 cells (60.5% ± 10.5% decrease; n = 5; p<0.001). Consistently, co-treatment with FK228 and anti-ANX-A1 mAb followed by washout of both compounds resulted in significantl repression of FK228-stimulated engulfment of leukemic cells by macrophages (54.1% ± 3.0% decrease; n = 5; p=0.02). This effect was not further enhanced by adding anti-ANX-A1 mAb to the co-culture medium, suggesting that membrane-associated but not soluble ANX-A1 contributes to leukemia cell engulfment by macrophages. Results presented here demonstrate a novel mechanism of action of HDAC inhibitors in the context of bone marrow microenvironment via histone acetylation, increased expression and externalization of ANX-A1, which provides an “eat-me” signal and mediates phagocytic clearance of apoptotic leukemic cells by macrophages. Our data further suggest that ANX-A1 is silenced via histone deacetylation in leukemic cells, and its re-expression by HDAC inhibitors may stimulate apoptosis in an autocrine fashion while diminishing the inflammatory response through activating phagocytosis in the bone marrow microenvironment.

scholarly journals Nature or Nurture? Role of the Bone Marrow Microenvironment in the Genesis and Maintenance of Myelodysplastic Syndromes

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 4116
Author(s):  
Syed A. Mian ◽  
Dominique Bonnet
Keyword(s):  
Bone Marrow ◽  
Clinical Phenotype ◽  
Bone Marrow Microenvironment ◽  
Haematopoietic Stem Cell ◽  
Bone Marrow Niche ◽  
Comprehensive Overview ◽  
Disease Outcomes ◽  
Limited Success ◽  
Hsc Transplantation

Myelodysplastic syndrome (MDS) are clonal haematopoietic stem cell (HSC) disorders driven by a complex combination(s) of changes within the genome that result in heterogeneity in both clinical phenotype and disease outcomes. MDS is among the most common of the haematological cancers and its incidence markedly increases with age. Currently available treatments have limited success, with <5% of patients undergoing allogeneic HSC transplantation, a procedure that offers the only possible cure. Critical contributions of the bone marrow microenvironment to the MDS have recently been investigated. Although the better understanding of the underlying biology, particularly genetics of haematopoietic stem cells, has led to better disease and risk classification; however, the role that the bone marrow microenvironment plays in the development of MDS remains largely unclear. This review provides a comprehensive overview of the latest developments in understanding the aetiology of MDS, particularly focussing on understanding how HSCs and the surrounding immune/non-immune bone marrow niche interacts together.

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.

Role of bone marrow microenvironment in myeloid leukemia progression

2015 ◽  
Vol 43 (9) ◽  
pp. S74
Author(s):  
Atul Kumar ◽  
Jina Bhattacharyya ◽  
Bithiah G. Jaganathan
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Bone Marrow Microenvironment

scholarly journals Targeting BMP signaling in the bone marrow microenvironment of myeloid leukemia

2020 ◽  
Vol 48 (2) ◽  
pp. 411-418 ◽  
Author(s):  
Sylvain Lefort ◽  
Véronique Maguer-Satta
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Bone Marrow Microenvironment ◽  
Bmp Signaling ◽  
Leukemic Cells ◽  
Hematopoietic Stem ◽  
Autocrine Loop ◽  
Bmp Pathway

The bone morphogenetic protein (BMP) pathway regulates the fate and proliferation of normal hematopoietic stem cells (HSC) as well as interactions with their niche. While BMP2 and BMP4 promote HSC differentiation, only BMP4 maintains HSC pool and favors interactions with their niche. In myeloid leukemia, we have identified intrinsic and extrinsic dysregulations of the BMP pathway in Chronic Myeloid Leukemia (CML) and Acute Myeloid leukemia (AML) responsible for leukemic stem cells (LSC) survival. In AML, BMP pathway alterations sustain and promote resistant immature-like leukemic cells by activating a new signaling cascade. Binding of BMP4 to BMPR1A leads to ΔNp73 expression, which in turn induces NANOG, altogether associated with a poor patient's prognosis. Despite efficient targeted therapies, like Tyrosine Kinase Inhibitors (TKI) in CML, many patients retain LSCs. Our laboratory demonstrated that the BMP pathway sustains a permanent pool of LSCs expressing high levels of BMPR1B receptor, that evolve upon treatment to progressively implement a BMP4 autocrine loop, leading to TKI-resistant cells. Single cell RNA-Seq analysis of TKI-persisting LSCs showed a co-enrichment of BMP with Jak2-signaling, quiescence and stem cell (SC) signatures. Using a new model of persisting LSCs, we recently demonstrated that BMPR1B+ cells display co-activated Smad1/5/8 and Stat3 pathways and could be targeted by blocking BMPR1B/Jak2 signal. Lastly, a specific BMPR1B inhibitor impaired BMP4-mediated LSC protection against TKIs. Altogether, data based on various studies including ours, indicate that BMP targeting could eliminate leukemic cells within a protective bone marrow microenvironment to efficiently impact residual resistance or persistence of LSCs in myeloid leukemia.

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 The Role of the Bone Marrow Microenvironment in the Response to Infection

2020 ◽  
Vol 11 ◽  
Author(s):  
Courtney B. Johnson ◽  
Jizhou Zhang ◽  
Daniel Lucas
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Immune Cells ◽  
Critical Role ◽  
Primary Source ◽  
Bone Marrow Microenvironment ◽  
Future Research ◽  
Multipotent Stem Cells ◽  
Hematopoietic Stem

Hematopoiesis in the bone marrow (BM) is the primary source of immune cells. Hematopoiesis is regulated by a diverse cellular microenvironment that supports stepwise differentiation of multipotent stem cells and progenitors into mature blood cells. Blood cell production is not static and the bone marrow has evolved to sense and respond to infection by rapidly generating immune cells that are quickly released into the circulation to replenish those that are consumed in the periphery. Unfortunately, infection also has deleterious effects injuring hematopoietic stem cells (HSC), inefficient hematopoiesis, and remodeling and destruction of the microenvironment. Despite its central role in immunity, the role of the microenvironment in the response to infection has not been systematically investigated. Here we summarize the key experimental evidence demonstrating a critical role of the bone marrow microenvironment in orchestrating the bone marrow response to infection and discuss areas of future research.

Sign in / Sign up

Export Citation Format

Share Document