Bone marrow blood vessels: normal and neoplastic niche

Blood vessels are among the most important factors in the transport of materials such as nutrients and oxygen. This study will review the role of blood vessels in normal bone marrow hematopoiesis as well as pathological conditions like leukemia and metastasis. Relevant literature was identified by a Pubmed search (1992-2016) of English-language papers using the terms bone marrow, leukemia, metastasis, and vessel. Given that blood vessels are conduits for the transfer of nutrients, they create a favorable situation for cancer cells and cause their growth and development. On the other hand, blood vessels protect leukemia cells against chemotherapy drugs. Finally, it may be concluded that the vessels are an important factor in the development of malignant diseases.

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Prognostic significance of mutated genes in megakaryocytic disorders

Oncology Reviews ◽

10.4081/oncol.2019.408 ◽

2019 ◽

Vol 13 (2) ◽

Author(s):

Ali Amin Asnafi ◽

Mohammad bagher Mohammadi ◽

Hadi Rezaeeyan ◽

Nader Davari ◽

Najmaldin Saki

Keyword(s):

Tumor Suppressor ◽

Tumor Suppressor Genes ◽

English Language ◽

Relevant Literature ◽

Prognostic Significance ◽

Suppressor Genes ◽

Diagnosis And Prognosis ◽

Pubmed Search ◽

Platelet Disorders

Megakaryopoiesis is a process during which platelets that play a major role in hemostasis are produced due to differentiation and maturation of megakaryocytic precursors. Several genes, including oncogenes and tumor suppressor genes, play a role in the regulation of this process. This study was conducted to investigate the oncogenes and tumor suppressor genes as well as their mutations during the megakaryopoiesis process, which can lead to megakaryocytic disorders. Relevant literature was identified by a PubMed search (1998-2019) of English language papers using the terms ‘Megakaryopoiesis’, ‘Mutation’, ‘oncogenes’, and ‘Tumor Suppressor’. According to investigations, several mutations occur in the genes implicated in megakaryopoiesis, which abnormally induce or inhibit megakaryocyte production, differentiation, and maturation, leading to platelet disorders. GATA-1 is one of the important genes in megakaryopoiesis and its mutations can be considered among the factors involved in the incidence of these disorders. Considering the essential role of these genes (such as GATA- 1) in megakaryopoiesis and the involvement of their mutations in platelet disorders, study and examination of these changes can be a positive step in the diagnosis and prognosis of these diseases.

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Platelet Extracellular Vesicles

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.314644 ◽

2020 ◽

Author(s):

Florian Puhm ◽

Eric Boilard ◽

Kellie R. Machlus

Keyword(s):

Bone Marrow ◽

Synovial Fluid ◽

Nucleic Acids ◽

Extracellular Vesicles ◽

Cell Communication ◽

Biological Processes ◽

Vascular Integrity ◽

Pathological Conditions ◽

Broad Array

Extracellular vesicles (EVs) are a means of cell-to-cell communication and can facilitate the exchange of a broad array of molecules between adjacent or distant cells. Platelets are anucleate cells derived from megakaryocytes and are primarily known for their role in maintaining hemostasis and vascular integrity. Upon activation by a variety of agonists, platelets readily generate EVs, which were initially identified as procoagulant particles. However, as both platelets and their EVs are abundant in blood, the role of platelet EVs in hemostasis may be redundant. Moreover, findings have challenged the significance of platelet-derived EVs in coagulation. Looking beyond hemostasis, platelet EV cargo is incredibly diverse and can include lipids, proteins, nucleic acids, and organelles involved in numerous other biological processes. Furthermore, while platelets cannot cross tissue barriers, their EVs can enter lymph, bone marrow, and synovial fluid. This allows for the transfer of platelet-derived content to cellular recipients and organs inaccessible to platelets. This review highlights the importance of platelet-derived EVs in physiological and pathological conditions beyond hemostasis.

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The Role of TWIST1 Gene Expression and Hypoxic Microenvironment in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.3839.3839 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3839-3839

Author(s):

Emilia Carolina Malafaia ◽

A. Mario Marcondes ◽

Ekapun Karoopongse ◽

Daniele Serehi ◽

Maria de Lourdes L. F. Chauffaille ◽

...

Keyword(s):

Gene Expression ◽

Cell Cycle ◽

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemia Cells ◽

Twist1 Expression ◽

Disease Biology ◽

Acute Myeloid

Abstract TWIST1, a basic helix-loop-helix (bHLH) transcription factor, plays a critical role in mesodermal development and organogenesis. Overexpressed TWIST1 has been thoroughly related to epithelial-mesenchymal transition (EMT) in solid tumors (QIN Q et al., 2012) and has been described as an emerging risk factor in hematological neoplasms (MERINDOL et al., 2014). . Many questions remain to be addressed concerning to the role of TWIST1 in acute myeloid leukemia (AML). The understanding of TWIST1 in leukemia cells and its interaction with microenvironment can offer new insights in regards to disease biology and therapeutic targets for patients with AML. Objectives: 1) to evaluate the role of stroma contact and hypoxia in TWIST1 expression in myeloid cell lines. 2) To evaluate the functional impact of overexpressing TWIST1 on KG1a and PL21 cells. 3) To evaluate TWIST1 expression in primary cells of AML patients. Methods: In order to mimic bone marrow microenvironment, myeloid cells were co-cultured with mesenchymal HS5 cell line and PO2 1% was established with Smart -Trak¨ 2 (Sierra Instruments, Inc.) equipment. Quantitative mRNA was determined using TaqMan¨ Universal Master Mix (Applied Biosystems, Foster City, CA) and 3-step standard cycling conditions with sequence-specific primer TWIST1 normalized to the expression of β-actin. KG1a and PL21 cells were transduced with lentivirus vector carrying e-GFP ("enhanced green fluorescence protein") for stable expression of TWIST1. Transduced cells were sorted by FITC fluorochrome and then verified through western blot analysis with TWIST1 antibody. For quantification of apoptosis, cells were labeled with PE-conjugated antibody using annexin V-phycoerythrin and propidium iodide (BD Biosciences, USA). DAPI (4',6- diamidino-2-phenylindole dihydrochloride) was used to stain DNA and determine cell cycle information . Apoptosis and cell cycle were analyzed by FACS -Becton Dickinson Canto II (BD Biosciences). Statistical analysis was assessed with unpaired t test. Results: Hypoxia induced TWIST1 mRNA expression in OCIAML3, PL21, KG1a and ML1 cell lines (fold-increased 46.3, 29.8, 12.9 and 2.3 respectively). Cells expressing endogenous TWIST1 protein (OCIAML3 and ML1) showed resistance to apoptosis in a hypoxic microenvironment (normoxia versus hypoxia: OCI/AML3, 22.6 % vs 11.7% and ML1, 29.8% vs. 7.5%) in contrast, cells not expressing endogenous TWIST1 protein (KG1a and PL21) went to apoptosis in the same conditions. Thus, overexpressing TWIST1 in KG1a and PL21 induced apoptosis protection in hypoxia (KG1a unmodified vs. modified: 17.6 ± 6.3 vs. 2.8 ± 6.3, p=0.04; PL21 unmodified vs. modified: 26.9 ± 10.9 vs. 3.2 ± 0.6, p=0.04) (fig 1). We found increased TWIST1 mRNA levels in bone marrow samples of 23 AML patients (3.88 ± 1.59) compared with 5 healthy controls (0.54 ±0.25) (p= 0.02) (fig 2). Patients in the highest tertile of TWIST1 expression did not show differences in percentage of blasts in bone marrow and complete remission after treatment compared with patients in low and middle tertile. Conclusion: Our data suggest TWIST1 gene expression protects acute myeloid leukemia cells from apoptosis in a hypoxic microenvironment. Moreover, our results showed increased expression of TWIST1 in AML patients. Thus, TWIST1 is a potential gene involved in leukemogenesis and should be further explored to understand disease biology and potential therapeutic targets. Disclosures No relevant conflicts of interest to declare.

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MBNL1 As a New Therapeutic Target in MLL-Fusion Gene Leukemia

Blood ◽

10.1182/blood.v126.23.462.462 ◽

2015 ◽

Vol 126 (23) ◽

pp. 462-462 ◽

Cited By ~ 2

Author(s):

Svetlana S Itskovich ◽

Jason Clark ◽

James C. Mulloy ◽

Matthew D Disney ◽

Ashish R Kumar

Keyword(s):

Bone Marrow ◽

Cord Blood ◽

Peripheral Blood ◽

Fusion Gene ◽

Leukemia Cell ◽

Leukemia Cells ◽

Transformed Cells ◽

Wild Type

Abstract Translocations of the Mixed Lineage Leukemia (MLL) gene located on chromosome 11 are commonly found in infants with AML or ALL and in secondary leukemia at all ages. A majority of patients with these translocations have a poor prognosis. Gene expression profiling studies demonstrate that one of the most consistently overexpressed genes in these leukemias (compared to all other leukemias) is muscleblind-like 1 (MBNL1). Further, MBNL1 was also identified as a direct transcriptional target of MLL-fusion proteins. An RNA-binding protein, MBNL1 is known to be a key factor in the pathophysiology of Myotonic Dystrophy Type I (DM), where sequestration of MBNL1 leads to splicing defects in muscle and neuronal cells. However, the role of MBNL1 in hematopoiesis and leukemogenesis is unknown. To determine the role of MBNL1 in normal hematopoiesis we studied MBNL1-/- mice. Compared to littermate controls, MBNL1-/- mice showed no differences in peripheral blood counts or bone marrow cellularity. When challenged with 5-FU, both MBNL1-/- and wild type mice displayed similar kinetics of peripheral blood cytopenia and recovery. Next we examined the role of MBNL1 in hematopoietic stem cell function using a competitive transplantation assay. Lethally irradiated mice were transplanted with a 1:1 mix of CD45.1 and CD45.2 bone marrow, with the latter being wild-type or MBNL1-/-. Flow cytometry analysis of peripheral blood at 4 weeks post-transplant showed donor chimerism being 53±4.14% in recipients of wild type marrow and 25±5.41 % in the MBNL1-/- recipients. Successive analyses every 4 weeks showed the chimerism to be stable over the next 16 weeks. To determine the role of MBNL1 in leukemia, we transformed MBNL1-/- or wild type bone marrow cells with various oncogenes delivered via retroviral transduction and compared them in methylcellulose colony replating assays. Absence of MBNL1 significantly reduced colony formation in MLL-AF9 and E2A-HLF transformed cells by 59.5% (± 27.1) and 50.7% (± 23) respectively, compared to controls. To assess the role of MBNL1 in leukemia in vivo, we transplanted MLL-AF9-transformed wild type or MBNL1-/- cells into irradiated mice. All recipients injected with wild-type MLL-AF9-transformed cells succumbed to leukemia with a median time of 106 days. In contrast, the majority of recipients of MBNL1-/- cells survived leukemia-free for at least 140 days post-transplantation (p=0.0017, log rank test). We next assessed the role of MBNL1 in human leukemia cells. Lentiviral-shRNA knockdown of MBNL1 in leukemia cell lines (MV4;11, THP-1) significantly inhibited cell growth, both in liquid culture and methylcellulose colony forming assays. To determine the requirement of MBNL1 for leukemia propagation in vivo, we used cord blood-derived leukemia cells bearing the MLL-AF9 fusion gene and mutant NRAS (MA9NRAS). MA9NRAS cells transduced with MBNL1-specific or control (non-targeting, NT) shRNA were transplanted into immunodeficient mice. Six weeks after transplant, bone marrow aspirates showed persistence of lentiviral-transduced cells in 85% of the NT-group. On the other hand, MBNL1-shRNA transduced cells were not detected in any of the recipient mice. These results suggest that MBNL1 is essential for leukemia cell propagation in vivo. Finally, we tested therapeutic targeting of MBNL1 in MLL-fusion gene leukemia. A lead inhibitor that prevents binding of MBNL1 to its targets was recently identified. Treatment of MA9NRAS cells with the inhibitor for 48 hours led to significant apoptosis whereas normal cord blood CD34+ cells were relatively less sensitive. Blockade of MBNL1 in leukemia cells either by shRNA-knockdown or by the inhibitor showed identical changes in splicing patterns of known MBNL1 target genes. Collectively, our data suggest that MBNL1 is required for the initiation and propagation of MLL-fusion gene leukemia while it appears relatively dispensable for normal hematopoiesis. Further, we have identified a promising lead inhibitor that could be developed for novel treatments for therapy-resistant leukemias. Disclosures No relevant conflicts of interest to declare.

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The Potential Role of the Six1/Eya1 Pathway in the Establishment of Leukemia Stem Cells in MLL-ENL – Induced Leukemia

Blood ◽

10.1182/blood.v118.21.1362.1362 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1362-1362 ◽

Cited By ~ 1

Author(s):

Sylvia Takacova ◽

Pavla Luzna ◽

Viktor Stranecky ◽

Vladimir Divoky

Keyword(s):

Bone Marrow ◽

Cellular Transformation ◽

Leukemia Cells ◽

Leukemia Stem Cells ◽

Transcription Profile ◽

Self Renewal ◽

Kinetics Of

Abstract Abstract 1362 During the multistep pathogenesis of acute leukemia (AL), a pool of leukemia stem cells (LSCs) emerges that is capable of limitless self-renewal and ensuring disease maintenance. The molecular mechanism that controls the kinetics of cellular transformation and development of LSCs is largely unknown. Using our MLL-ENL-ERtm mouse model, we have previously shown (Takacova et al., Blood 2009, 114 (22): 947–947, ASH abstract) activation of the ATR/ATM-Chk1/Chk2-p53/p21 checkpoint leading to senescence at early stages of cellular transformation (myeloproliferation), thereby preventing AL development in vivo. Experimental ATM/ATR inhibition accelerated the transition to immature cell states, acquisition of LSC properties and AL development in these mice. The MLL-ENL-ERtm mouse model allows us to study the kinetics of MLL-ENL-ERtm LSC development. We raised the questions how the transformation process progresses from the pre-LSC to the LSC state, and how DNA damage response (DDR) - mediated senescence affects the transition in gene expression. Given that the threshold of DDR signaling events is rate-limiting, we determined the transcription profile of the pre- LSC–enriched cell states derived from bone marrow and spleen of the MLL-ENL-ERtm mice at the early disease stage, and we correlated this transcription profile with the level of DDR, proliferation rate and induction of senescence. Pair-wise comparisons revealed up-regulation of the Six1 transcription factor gene and its cofactor Eya1 in the MLL-ENL-ERtm pre-LSCs in association with aberrant proliferation in both tissues. The notable difference between the two tissues concerning the barrier induction was the higher threshold of DDR and senescence in the bone marrow due to cooperation with inflammatory cytokines that fine-tune the DDR level. Interestingly, the expression of Six1 and Eya1 genes was down-regulated in senescence exclusively in the bone marrow. Consistent with these in vivo data, we found Six1 expression decreased in response to inflammation/DDR-induced senescence in the MLL-ENL-ERtm bone marrow cells cultured in vitro and correlated with SA-beta-gal positivity and p16 up-regulation. Six1 mRNA level was decreased only transiently after ionizing radiation (4 Gy)-induced DDR in the same cell line. These data suggest that Six1 expression is down-regulated in response to high DDR and permanent cell-cycle arrest in the MLL-ENL-ERtm pre-LSCs. Furthermore, we identified the transcription profile of the LSC-enriched cell state after inhibition of DDR in caffeine-treated MLL-ENL-ERtm mice in vivo. Interestingly, the expression level of Six1 and Eya1 was significantly increased in the bone marrow and spleen of the MLL-ENL-ERtm AML mice compared to the early (preleukemia) stage. High expression of Six1 and Eya1 and higher cell number expressing these genes was further confirmed by immunohistochemical staining on tissue sections. The MLL-ENL-ERtm LSC-enriched spleen cells showed increased colony forming ability in vitro and leukemia-initiating potential in serial transplantation experiments compared to pre-LSCs. Moreover, we detected Six1 and Eya1 expression in the infiltrating leukemia cells in tissues of the caffeine-treated MLL-ENL-ERtm AML mice and in a subset of leukemia cells in transplanted mice. Based on these findings and correlations, we hypothesized that the Six1/Eya1 pathway might be involved in regulation of some of the aspects of LSC development as well as invasion and maintenance of leukemia in our MLL-ENL-ERtm mice. Notably, our data indicate that senescence represses a subset of the MLL-ENL-downstream transcription response and prevents full activation of self-renewal. Experiments leading to more detailed understanding of the role of the Six1/Eya1 pathway in the MLL-ENL-induced cellular transformation are ongoing. Disclosures: No relevant conflicts of interest to declare.

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Bone Marrow Macrophage Galectin-3 Regulates Platelet Production through Recognition of O-Glycans on Megakaryocytes

Blood ◽

10.1182/blood.v128.22.409.409 ◽

2016 ◽

Vol 128 (22) ◽

pp. 409-409

Author(s):

Melissa M Lee-Sundlov ◽

Renata Grozovsky ◽

Silvia Giannini ◽

Martina McGrath ◽

Haley E Ramsey ◽

...

Keyword(s):

Bone Marrow ◽

Antigen Expression ◽

Blood Platelet ◽

Activated Macrophages ◽

Bone Marrow Macrophage ◽

Platelet Production ◽

Platelet Counts ◽

Pathological Conditions ◽

Galectin 3

Abstract Bone marrow (BM) macrophages maintain both survival and retention of hematopoietic stem cells and regulate erythropoiesis. The role of macrophage lectins and glycans in thrombopoiesis remains unclear. We report a novel role for bone marrow macrophage galectin-3 in maintaining platelet counts, by phagocytosing megakaryocytes (MKs) expressing the Thomsen-Friedenreich (TF) antigen, which is often exposed under pathological conditions, such as cancer and malignancies. The TF antigen is a disaccharide presented in cryptic form on O-glycans and covered by a sialic acid moiety. The sialyltransferase ST3Gal1 transfers sialic acid onto the TF antigen. To investigate the role of O-glycans in thrombopoiesis, we generated mice with increased TF antigen in MKs by generating St3gal1loxP/PF4+ mice specifically lacking ST3Gal1 in the MK lineage. As expected, St3gal1loxP/PF4+ circulating platelets and BM MKs had increased TF antigen expression, compared to controls, as evidenced by peanut agglutinin (PNA) binding. Other blood cell lineages had no increase in TF antigen expression. St3gal1loxP/PF4+ mice developed mild thrombocytopenia, but surprisingly had virtually normal platelet clearance. BM MK colony forming units and in vitro proplatelet production were normal in St3gal1loxP/PF4+ mice, suggesting that extrinsic factors in the St3gal1loxP/PF4+BM environment affected platelet production. St3gal1loxP/PF4+ BM smears revealed increased hemophagocytosis, indicative of an increase in phagocytic macrophages. In vivo macrophage ablation by injection of clodronate-encapsulated liposomes significantly reduced the numbers of activated macrophages, thereby normalizing blood platelet counts and size. Flow cytometric phenotypic analysis of BM-derived macrophages showed an increased population of activated macrophages in St3gal1loxP/PF4+ mice, compared to controls, specifically macrophages with increased galectin-3 expression, a ligand for the TF antigen. Immunofluorescence staining of BM sections using a specific antibody towards the TF antigen showed that MK progenitors and pro-platelet-like structures expressed TF antigen in control BMs, which is significantly increased in St3gal1loxP/PF4+ mice and co-localized with galectin-3 expressing macrophages, supporting the notion that MK O-glycans and macrophage galectin-3 play a role in thrombopoiesis under steady state and pathological conditions. Consistent with this notion, galectin-3 deficient mice have slightly, but significantly increased blood platelet counts. We conclude that galactin-3 plays a minor role in normal thrombopoiesis. Activation of galectin-3 expressing macrophages by the MK TF antigen leads to MK phagocytosis, inhibition of platelet formation and thrombocytopenia. Disclosures No relevant conflicts of interest to declare.

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Both Arid1b and Arid2 Are Tumor Suppressors in MLL-AF9 Leukemogenesis

Blood ◽

10.1182/blood-2019-127123 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1248-1248

Author(s):

Theresa Bluemn ◽

Jesse Schmitz ◽

Yongwei Zheng ◽

Nan Zhu

Keyword(s):

Bone Marrow ◽

Tumor Suppressor ◽

Disease Burden ◽

Cre Recombinase ◽

Leukemia Cells ◽

Control Cohort ◽

Wild Type ◽

Cell Frequency

ATP-dependent chromatin remodeling complexes, including BAF (BRG1 associated factor) and PBAF (Polybromo-associated BRG1 associated factor), play major roles in development and disease. These complexes contain multiple subunits and utilize ATP to remodel nucleosomes and, as a result, affect downstream processes. Subunits of the BAF and PBAF complexes are frequently mutated in various cancers, including in acute myeloid leukemia. However, the role of distinct members of these complexes in leukemogenesis is poorly understood. BAF and PBAF complexes are distinguished from each other by unique AT-rich interacting domain (ARID) subunits, ARID1A/B and ARID2, respectively. Recently, Arid2 was suggested to have tumor suppressive functions in MLL-AF9 leukemogenesis, however the role of Arid1b is unknown. In this study, we further evaluated the tumor suppressor roles of Arid2 and Arid1b in MLL-AF9 leukemogenesis. To study the effect of the loss of Arid2 and Arid1b on MLL-AF9 leukemia in vitro, hematopoietic stem and progenitor cells from Arid1bfl/fl, Arid2fl/fl and wild type (control) mice were transformed by retroviral expression of MLL-AF9. Arid1b or Arid2 was then deleted by retroviral delivery of Cre-recombinase and cellular phenotypes were characterized by flow cytometry. In vitro characterization revealed Arid1b-/-and Arid2-/-MLL-AF9 cells have similar growth rates to control cells and no changes in cell cycle status and apoptosis. To study leukemogenesis in vivo, two hematopoietic specific conditional knockout mouse models, Vav1Cre, a constitutively active Cre-recombinase, and Mx1Cre, an inducible Cre-recombinase, were used. Primary and secondary transplant recipient mice were assessed for survival, disease burden, and leukemia stem cell frequency. In primary transplantation, leukemic initiation was not altered by the loss of the Arid2. Overall survival of primary recipients and disease burden in moribund mice (percentage of GFP positive MLL-AF9 cells in bone marrow/spleen and spleen weight) were similar to control counterparts. However, in limiting dilution secondary transplantation of Arid2fl/flVav1Cre (Arid2-/-) and wild type Vav1Cre (control) MLL-AF9, median survival of the Arid2-/- cohort decreased 1 to 2 weeks in comparison to the control cohort and there was a two-fold increase in leukemia initiating cell frequency upon deletion of Arid2. Together these results support the previous indication that Arid2 is a tumor suppressor in MLL-AF9 leukemic initiation. To gain insight into the function of Arid1b in MLL-AF9 leukemogenesis, we performed primary transplantation of Arid1bfl/flcells transduced with MLL-AF9. Our data showed that loss of Arid1b enhanced leukemic initiation in the MLL-AF9 leukemia model. One-month post induction with pIpC, Arid1bfl/fl Mx1Cre MLL-AF9 cells accumulated faster in the peripheral blood and primary recipients exhibited decreased median survival compared with wild type Mx1Cre controls. Percentage of GFP+ leukemia cells was higher in the spleen of moribund mice in the Arid1bfl/fl Mx1Cre cohort, compared with the control cohort. Taken together, our data suggests Arid1b, in addition to Arid2, acts as a potential novel tumor suppressor in MLL-AF9 leukemogenesis. To study the mechanism of Arid1b and Arid2's function in MLL-AF9 leukemogenesis, RNA-sequencing of leukemic bone marrow cells was conducted. Consistent with the previous study, Arid2 null leukemia cells had increased Gata2 expression and decreased p57 expression. Gene Set Enrichment Analysis of Arid1b null cells showed enrichment of oncogenic signatures including ATM, Cyclin D and macrophage development as potentially contributing to the underlying tumor suppressive mechanism of Arid1b. In summary, our study uncovered Arid1b, in addition to Arid2, as a potential novel tumor suppressor in MLL-AF9 leukemia. Our study, together with published studies on the requirement of other subunits (SMARCA4, SMARCD2 and DPF2) of the BAF and PBAF complexes in MLL-AF9 leukemia, reveal opposing roles of the components of the BAF and PBAF complexes in leukemogenesis, the mechanism of which require further investigation. Disclosures No relevant conflicts of interest to declare.

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TRYPTOPHAN: A KEY METABOLITE OF HOMEOSTASIS AND A REGULATOR OF BODY FUNCTIONS

Hepatology and Gastroenterology ◽

10.25298/2616-5546-2021-5-2-143-149 ◽

2021 ◽

Vol 5 (2) ◽

pp. 143-149

Author(s):

V. M. Sheibak ◽

◽

A. Yu. Pauliukavets ◽

Keyword(s):

Intestinal Microbiota ◽

English Language ◽

Tryptophan Metabolism ◽

Biologically Active ◽

Receptor Ligands ◽

Aryl Hydrocarbon ◽

Pathological Conditions ◽

Tryptophan Metabolites ◽

Important Therapeutic Target

Background. Tryptophan is an essential amino acid found mainly in protein foods and its availability is highly dependent on a diet. A significant part of tryptophan is metabolized in the gastrointestinal tract by the intestinal microbiota, producing a number of biologically active molecules, including aryl hydrocarbon receptor ligands, kynurenines, and serotonin (5-hydroxytryptamine). Objective. To analyze scientific studies confirming the key role of tryptophan microbial catabolites on the function of a macroorganism. Material and methods. The analysis of 47 English-language literature sources containing information on the effects of tryptophan metabolites on the mammalian organism was carried out. Results. It has been established that tryptophan metabolism plays a central role both in a normal macroorganism and in pathological conditions, it being directly or indirectly controlled by the intestinal microbiota. Conclusions. Thus, tryptophan metabolism is an important therapeutic target, underutilized in the treatment of a number of chronic neurological pathologies and immunocompetent conditions. An important factor is the use of nutraceuticals and probiotics by microorganisms that modulate the metabolism of tryptophan in the intestine and stimulate the synthesis of specific metabolites.

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