Synergistic activity of Herbal Extracts on Dog Blood Progenitor cells.

2017 ◽  
Vol 04 (01) ◽  
pp. 01-05 ◽  
Keyword(s):  
Progenitor Cells ◽  
Synergistic Activity ◽  
Herbal Extracts ◽  
Dog Blood

scholarly journals Evaluation and Comparison of Antibacterial Efficacy of Herbal Extracts in Combination with Antibiotics on Periodontal pathobionts: An in vitro Microbiological Study

Antibiotics ◽  
2019 ◽  
Vol 8 (3) ◽  
pp. 89 ◽  
Author(s):  
Shahabe Abullais Saquib ◽  
Nabeeh Abdullah AlQahtani ◽  
Irfan Ahmad ◽  
Mohammed Abdul Kader ◽  
Sami Saeed Al Shahrani ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Plant Extracts ◽  
Pathogenic Bacteria ◽  
Bacterial Resistance ◽  
Antimicrobial Agents ◽  
Synergistic Activity ◽  
Antibacterial Efficacy ◽  
Herbal Extracts ◽  
Inhibition Zones

Background: In the past few decades focus of research has been toward herbal medicines because of growing bacterial resistance and side effects of antimicrobial agents. The extract derived from the plants may increase the efficacy of antibiotics when used in combination against pathogenic bacteria. In the current study, the synergistic antibacterial efficacy of plant extracts in combination with antibiotics has been assessed on selected periodontal pathogens. Methods: Ethanolic extracts were prepared from Salvadora persica (Miswak) and Cinnamomum zeylanicum (Ceylon cinnamon), by the soxhalate method. Plaque samples were collected from clinical periodontitis patients to isolate and grow the periodontal pathobionts under favorable conditions. Susceptibility of bacteria to the extracts was assessed by gauging the diameter of the inhibition zones. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of plant extracts were determined against each bacterium. Synergistic activity of plants extract in combination with antibiotics against the bacteria was also assessed by measuring the diameter of the inhibition zones. Results: Ethanolic extract of both the plants showed an inhibitory effect on the proliferation and growth of all four strains of periodontal pathobionts. Maximum antibacterial activity was exhibited by C. zeylanicum against Tannerella forsythia (MIC = 1.56 ± 0.24 mg/mL, MBC = 6.25 ± 0.68 mg/mL), whereas among all the studied groups the minimum activity was reported by C. zeylanicum against Aggregatibacter actinomycetemcomitans the (MIC = 12.5 ± 3.25 mg/mL, MBC = 75 ± 8.23 mg/mL). Combination of herbal extracts with different antibiotics revealed a synergistic antibacterial effect. The best synergism was exhibited by S. persica with metronidazole against A. actinomycetemcomitans (27 ± 1.78). Conclusions: Current in vitro study showed variable antibacterial activity by experimented herbal extracts against periodontal pathobionts. The synergistic test showed significant antibacterial activity when plant extracts were combined with antibiotics.

Synergistic Activity of Combinations of JAK2 Kinase Inhibitor with PI3K/mTOR, MEK or PIM Kinase Inhibitor Against Human Myeloproliferative Neoplasm Cells Expressing JAK2V617F

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 798-798 ◽  
Author(s):  
Warren Fiskus ◽  
Rekha Rao Manepalli ◽  
Ramesh Balusu ◽  
Kapil N. Bhalla
Keyword(s):  
Progenitor Cells ◽  
Mtor Inhibitor ◽  
Kinase Inhibitor ◽  
Jak2 V617f ◽  
Protein Translation ◽  
Mek Inhibitor ◽  
Cytokine Signaling ◽  
Synergistic Activity ◽  
Cytotoxic Effects ◽  
Pim1 Kinase

Abstract Abstract 798 The mutant JAK2-V617F tyrosine kinase (TK) is present in the majority of patients with BCR-ABL negative myeloproliferative neoplasms (MPNs). JAK2-V617F activates downstream signaling through the STAT, RAS/MAPK and PI3/AKT pathways, conferring proliferative and survival advantages in the MPN hematopoietic progenitor cells (HPCs). We have previously reported that pan-histone deacetylase (HDAC) inhibitors e.g. panobinostat (PS) (Novartis Pharmaceuticals), depleted mRNA expression of JAK2-V617F, and disrupted the chaperone association of with hsp90 with JAK2-V617F, thereby promoting the degradation of JAK2-V617F by the proteasome. This led to attenuation of the levels and downstream transcriptional activity of STAT3 and STAT5, resulting in growth arrest and apoptosis of MPN HPCs. Additionally, co-treatment with PS and a JAK2 kinase inhibitor, TG101209, further depleted JAK/STAT signaling and synergistically induced apoptosis of JAK2-V617F expressing HEL92.1.7 and Ba/F3-JAK2V617F cells, as well as exerted greater lethality against primary CD34+CD38-Lin- MPN versus normal CD34+ HPCs. In the present studies, we determined the cytotoxic effects of inhibiting JAK2-STAT3/5 in conjunction with pharmacologic targeting of the collateral, pro-growth and pro-survival signaling through PI3K/AKT, RAF-MEK or PIM1 kinases in MPN cells. For this, the cytotoxic effects of co-treatment with TG101209 and the MEK inhibitor (AZD6244, AstraZenaca), dual PI3K/mTOR inhibitor (BEZ235, Novartis) or the PIM1 kinase inhibitor (SGI-1776, SuperGen) were evaluated in HEL92.1.7, Ba/F3-JAK2V617 and primary human MPN cells. Treatment with BEZ235 dose-dependently attenuated the levels of p-JAK2, p-STAT5, p-STAT3, p-AKT, p-ERK1/2 and p-4EBP1. Co-treatment with BEZ235 and TG101209 was synergistically lethal against the cultured MPN and primary CD34+ MF-MPN cells (combination indices < 1.0). Co-treatment with AZD6244 and TG101209 also induced synergistic apoptosis of cultured MPN cells (combination indices of < 1.0). This was associated with greater attenuation of the levels of p-AKT and p-ERK1/2. PIM1 is a cytoplasmic serine/threonine kinase that serves as a downstream effector of several cytokine signaling pathways promoting cell survival and proliferation. PIM1 collaborates in Myc-induced transformation and known to phosphorylate 4EBP1 and eIF4B, thereby promoting protein translation. Co-treatment with TG101209 and the PIM1 kinase inhibitor, SGI-1776 also induced synergistic apoptosis of HEL92.1.7 cells and Ba/F3-JAK2V617F cells (combination indices < 1.0) but not of Ba/F3-hEpoR cells. PIM kinase mediates PRAS40 phosphorylation and induces mTORC1 activity in phosphorylating 4EBP1. Consistent with this, co-treatment with SGI-1776 and TG-101209 inhibited p-PRAS40 and p-4EBP1 levels in cultured MPN but not in normal progenitor cells. These findings demonstrate for the first time that combined treatment with a MEK inhibitor, PIM1 kinase inhibitor or dual PI3K/mTOR inhibitor enhances the anti-JAK2-V617F activity of TG101209 in cultured and primary human MPN cells. Our findings support the rationale to determine the in vivo activity of TG101209 in combination with inhibitors of MEK, PIM1 or PI3K/mTOR kinase against human MPN cells. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Partial purification and characterization of a growth factor for macrophage progenitor cells with high proliferative potential in mouse bone marrow

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 503-508
Author(s):  
AB Kriegler ◽  
TR Bradley ◽  
E Januszewicz ◽  
GS Hodgson ◽  
EF Elms
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Proteolytic Enzymes ◽  
Partial Purification ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Synergistic Activity ◽  
Human Spleen

A population of macrophage progenitor cells, with high proliferative potential, has recently been demonstrated in postfluorouracil-treated and normal mouse bone marrow (BM) in vitro, when the newly discovered growth factor (synergistic activity, SA) is combined with a macrophage colony-stimulating factor (CSF) as a proliferative stimulus. SA, shown to be present in human spleen and placental conditioned media (HSCM and HPCM, respectively) have been studied and found to be unstable to trypsin digestion and to heating at 50 degrees C or above; stable between pH 4 and 9; nonadherent to Con-A-Sepharose; and to have an isoelectric point between pH 5 and 5.8 and a molecular weight of between 14,000 and 21,000 as indicated by gel filtration chromatography. SAs from both HSCM and HPCM have been purified 89- and 122-fold, respectively, by precipitation of extraneous proteins at pH 5 followed by chromatographing twice on Sephacryl S200. Neither of these partially purified SAs contain any CSF for mouse BM. These results indicate that the SAs from HSCM and HPCM may be closely related and that they are structurally different from CSFs derived from various murine sources that have been shown to be stable to proteolytic enzymes and heat.

Mobilization and transplantation of Philadelphia-negative peripheral-blood progenitor cells early in chronic myelogenous leukemia.

1997 ◽  
Vol 15 (4) ◽  
pp. 1575-1582 ◽  
Author(s):  
A M Carella ◽  
I Cunningham ◽  
E Lerma ◽  
A Dejana ◽  
F Benvenuto ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Chronic Myelogenous Leukemia ◽  
Peripheral Blood ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Cytolytic Activity ◽  
Myelogenous Leukemia ◽  
Synergistic Activity ◽  
Ifn Alpha ◽  
Peripheral Blood Progenitor Cells

PURPOSE Mobilization of Philadelphia (Ph) chromosome-negative progenitors is now possible in many Ph1-positive chronic myelogenous leukemia (CML) patients who had received interferon alfa (IFN-alpha) with no cytogenetic response. In this pilot study, we used this approach in patients without prior IFN-alpha therapy to determine if the number and quality of mobilized progenitors would be increased and to evaluate the potential effect of these cells as autografts. PATIENTS AND METHODS Twenty-two untreated patients were mobilized within 12 months of diagnosis. The treatment regimen consisted of the mini-ICE protocol. Beginning on day +8, granulocyte colony-stimulating factor (G-CSF) was used in all patients. Leukophoresis was performed as the patients were recovering from aplasia, when WBC count exceeded 0.8 x 10(9)/L. RESULTS In 14 patients, (63%) the leukophoresis product was entirely Ph1-negative and in four patients the Ph1-positive cell rate was < or = 7%. Significant numbers of long-term culture-initiating cells (LTC-IC) and CD34+ Thy1+Lin- cells were found in most of the Ph1-negative collections that were tested. Twelve patients underwent autografting with their mobilized peripheral-blood progenitor cells (PBPC) (Ph1-negative collections, 10 patients; major cytogenetic response, two patients). All patients engrafted and are alive; six have Ph1-negative marrow 7 to 15 months after autografting. Posttransplant treatment was IFN-alpha combined with interleukin (IL)-2 because of the recent demonstration of synergistic activity in augmenting cytolytic activity. CONCLUSION Intensive chemotherapy given in early chronic phase of CML is well tolerated and results in high numbers of circulating Ph1-negative precursor cells.

scholarly journals The effect of prostaglandins E1 and E2 on macrophage progenitor cells with high proliferative potential in mouse bone marrow in vitro

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1348-1352
Author(s):  
AB Kriegler ◽  
TR Bradley ◽  
GS Hodgson
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Synergistic Activity ◽  
Agar Culture ◽  
Inhibition Of Proliferation ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

High proliferative potential macrophage progenitor cells (HPP-CFC) in 5- fluorouracil (FU) treated and normal mouse bone marrow (BM) have been shown to be less sensitive to inhibition of proliferation by prostaglandins of the E series (PGE) than low proliferative potential macrophage progenitor cells (LPP-CFC) in normal BM in agar cultures. The growth of large colonies (diameter greater than 0.5 mm) derived from HPP-CFC in FU BM, which require a combination of macrophage colony- stimulating factor (CSF-1) plus a new growth factor called synergistic activity (SA), are inhibited by 50% in the presence of 5.5 X 10(-6) M PGE1. On the other hand, LPP-CFC in normal BM, which form smaller colonies (diameter less than or equal to 0.5 mm) in the presence of CSF- 1 alone, require only 5 X 10(-8) M PGE1 for the same level of inhibition. Addition of appropriate concentrations of PGE1 to the agar culture assay should improve detection of HPP-CFC by inhibiting the proliferation of LPP-CFC. These observations suggest that the apparent negative feedback control of macrophage production by PGE operates largely on the LPP-CFC, which respond to CSF-1 alone, and is probably not involved in the regulation of the more primitive HPP-CFC.

scholarly journals Clinical-Stage Menin Inhibitor KO-539 Is Synergistically Active with Multiple Classes of Targeted Agents in KMT2A-r and NPM1-Mutant AML Models

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3357-3357
Author(s):  
John A. Davis ◽  
Warren C. Fiskus ◽  
Naval Daver ◽  
Christopher Peter Mill ◽  
Christine Birdwell ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Board Of Directors ◽  
Research Funding ◽  
Synergistic Activity ◽  
Research Support ◽  
Advisory Committees ◽  
Protein Levels ◽  
N Terminus ◽  
Pdx Models

Abstract The N-terminus of the histone-lysine-N-methyltransferase MLL1 (KMT2A) contains the menin binding domain (MBD). Menin is a scaffold protein that binds to MBD and tethers MLL1 to chromatin. The Menin-KMT2A complex regulates expression of the leukemogenic homeobox A9 (HOXA9) gene and its co-factor MEIS1 in myeloid stem progenitor cells. In MLL-rearranged (MLL-r) AML, the N-terminus of the KMT2A gene is fused to the C-terminus of any of over 80 fusion partners, most commonly AF4, AF9, ENL and ELL. These MLL fusion partners are components of (and recruit) the super elongation complex and DOT1L to induce H3K4Me3 and H3K79Me2 marks on active chromatin, driving aberrant expression of HOXA9, MEIS1, PBX3, MEF2C and CDK6. In AML with mutant NPM1 (NPM1c), the wild type menin-KMT2A complex is the main oncogenic driver of HOXA9, MEIS1 and FLT3, promoting self-renewal of mutant leukemic blasts. KO-539 is a novel, oral investigational drug candidate targeting the Menin-KMT2A protein-protein interaction. Preclinical data show that KO-539 and close analogs induce differentiation and loss of viability of AML cells, and exert profound anti-leukemic activity in multiple PDX models harboring MLL-FP or NPM1c when dosed continuously QD for 3-6 weeks. In an ongoing phase 1/2A KOMET-001 clinical trial (NCT04067336) evaluating KO-539 in adult patients with relapsed and/or refractory AML, significant biological activity as well as complete remission lacking minimal residual disease have been observed. The present studies were focused on further elucidating biologic effects and on determining synergistic activity of KO-539 with agents targeting BCL2, BET proteins and CDK6. Treatment with KO-539 dose-dependently inhibited in vitro growth, as well as induced differentiation (by both morphology and increased CD11b expression) and loss of viability of MOLM13 (MLL-AF9 and FLT3-ITD) and OCI-AML3 (NPM1c and homozygous NRAS mutation) cells and patient-derived (PD) MLL-r or NPM1c AML cells. This was associated with repression of MEIS1, PBX3, MEF2C, FLT3, MYC, BCL2 and CDK6 transcription but increased mRNA expression of ITGAM (CD11b). KO-539 treatment also dose-dependently depleted protein levels of Menin, MEIS1, FLT3, CDK6 and BCL2, but upregulated MCL1 and CD11b proteins in MOLM13 and OCI-AML3 cells. Mass cytometry (CyTOF) analysis of PD MLL-r and NPM1c AML samples confirmed that, following KO-539 treatment there was also decline in protein levels of Menin, MEIS1, MEF2C, PBX3, FLT3, CDK6 and BCL2 in phenotypically characterized AML stem cells (with high expression of CLEC12A, CD123, CD244, CD99, but low expression of CD11b). KO-539-mediated Menin depletion was associated with polyubiquitylation and proteasomal degradation of Menin protein, given that protein levels were restored by co-treatment with the proteasome inhibitor carfilzomib. Notably, co-treatment (in vitro) with KO-539 in combination with venetoclax, OTX015 (pan-BET inhibitor) or abemaciclib (CDK6 inhibitor) for 72 to 96 hours induced synergistic loss of viability in cultured cell lines and PD AML cells from both MLL-r and NPM1c AML but not normal CD34+ progenitor cells or AML cells lacking MLL-FP or NPM1c, as determined by the SynergyFinder algorithm. Findings of ongoing in vivo studies determining effects of treatment with KO-539 and/or venetoclax or OTX015, versus vehicle control in PDX models will be presented at the meeting. These preclinical findings highlight the molecular correlates of anti-AML efficacy of KO-539 and demonstrate potentially synergistic KO-539-based combinations with inhibitors of BCL2, BET proteins and CDK6 against MLL-r or NPM1 mutant AML. Disclosures Daver: Bristol Myers Squibb: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Novimmune: Research Funding; FATE Therapeutics: Research Funding; Genentech: Consultancy, Research Funding; Glycomimetics: Research Funding; Amgen: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Kadia: Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Amgen: Other: Grant/research support; BMS: Other: Grant/research support; Cure: Speakers Bureau; Genentech: Consultancy, Other: Grant/research support; Dalichi Sankyo: Consultancy; AstraZeneca: Other; Astellas: Other; Genfleet: Other; Ascentage: Other; Cellonkos: Other; Sanofi-Aventis: Consultancy; Pulmotech: Other; Jazz: Consultancy; Liberum: Consultancy; Novartis: Consultancy; Pfizer: Consultancy, Other. DiNardo: Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Novartis: Honoraria; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Leoni: Kura Oncology: Current Employment. Burrows: Kura Oncology: Current Employment.

Combined Therapy With BRD4 Antagonist and FLT3 Inhibitor Exerts Synergistic Activity Against Cultured and Primary AML Blast Progenitors Expressing FLT-ITD

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3821-3821
Author(s):  
Melissa Rodriguez ◽  
Warren Fiskus ◽  
Sunil Sharma ◽  
Jun Qi ◽  
John A Valenta ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Conflicts Of Interest ◽  
Activation Loop ◽  
Synergistic Activity ◽  
Gene Promoters ◽  
Histone Proteins ◽  
Cellular Models ◽  
Induced Apoptosis

Abstract Mutations in FLT3 are detected in approximately 30% of AML and are associated with poor overall survival. Although first (PKC412, sorafenib and CEP701) and second generation (AC220) FLT3 tyrosine kinase inhibitors (TKI) induce remissions, resistance-causing gatekeeper (F691I/L), activation loop (AL) mutations (D835V/Y/F) or compound FLT3-ITD/F691I AL mutations are known to impair the in vitro and in vivo activity of the FLT3-TKIs. The BET (bromodomain and extraterminal) protein family members including BRD4 bind to acetylated lysines on the histone proteins, help assemble transcriptional regulators at the target gene promoters and enhancers, and regulate the expression of important oncogenes, e.g., MYC and BCL-2. BRD4 antagonists JQ1 and I-BET151 disrupt the binding of the bromodomain of BRD4 to acetylated lysines on histone proteins, thereby inhibiting expressions of c-MYC and BCL-2 and inducing apoptosis of AML cells. Based on this, we evaluated the in vitro and in vivo activity of JQ1 and FLT3 antagonists AC220 and ponatinib against cultured mouse lymphoid (Ba/F3/FLT3-ITD), as well as human cultured (MOLM13 and MV4-11) and primary AML blast progenitor cells (BPCs) expressing FLT3-ITD. JQ1, but not its inactive enantiomer R-JQ1, potently induced apoptosis of not only Ba/F3/FLT3-ITD but also of Ba/F3/FLT3-ITD expressing the highly FLT3 TKI-resistant mutations F691L and D835V (IC50 values for JQ1 were 697, 1588 and 909 nM, in the three cell lines, respectively). This was associated with attenuation of c-MYC, but the induction of BIM levels. Both JQ1 and I-BET151 dose-dependently induced apoptosis of MOLM13 and MV4-11 cells, as well as of primary AML BPCs expressing FLT3-ITD. Concomitantly, JQ1 treatment attenuated c-MYC, BCL2 and CDK6, while inducing p21, p27, BIM and cleaved PARP levels. JQ1 and I-BET151 did not induce apoptosis of CD34+ normal bone marrow progenitor cells. Following engraftment of NOD/SCID mice with MOLM13 cell xenograft, treatment with JQ1 (50 mg/kg, formulated in 10% 2-hydroxypropyl-β-cyclodextrin, daily x 5 days per week x 3 weeks), versus treatment with vehicle control, significantly improved survival of the mice (p< 0.05), without causing any toxicity. This was associated with the in vivo attenuation of c-MYC and BCL-2 levels in the harvested AML cells from the mice. Co-treatment with JQ1 or I-BET151 and FLT3 antagonist AC220 or ponatinib synergistically induced apoptosis of MOLM13 and MV4-11 cells. This was associated with greater reduction in the levels of MYC, BCL2 and CDK6, but more induction of BIM, p27 and cleaved PARP levels. Knockdown of BRD4 by treatment with specific shRNA phenocopied the effects of JQ1 and sensitized MOLM13 cells to ponatinib and AC220. As compared to each agent alone, treatment with JQ1 and ponatinib or AC220 also induced more apoptosis of primary AML BPCs expressing FLT3-ITD, associated again with greater reduction of the levels of MYC, BCL2 and CDK6, but more induction of BIM, p27 and cleaved PARP levels. We also determined the effects of JQ1 against MOLM13/TKIR cells that were generated under the continuous selection pressure of FLT3 TKI, and exhibited > 10 fold resistance to ponatinib but > 50 fold resistance to AC220. Importantly, as compared to the parental MOLM13, the MOLM13/TKIR cells were markedly more sensitive to JQ1-induced apoptosis (p< 0.001). Additionally, co-treatment with JQ1 and ponatinib but not AC220 synergistically induced apoptosis of MOLM13/TKIR cells. Supporting our previous findings (Blood. 2005;105:1768) that FLT3-ITD is a heat shock protein (hsp) 90 client-oncoprotein, the non-geldanamycin hsp90 inhibitor AUY922 was equally effective in inducing apoptosis of MOLM13 versus MOLM13/TKIR cells. Collectively, these findings demonstrate that BRD4 antagonist exhibits potent activity against cultured and primary AML cells expressing FLT-3-ITD, as well as against cellular models of FLT3 with gate-keeper and activation loop mutations. These findings also highlight the novel and synergistic activity of the combination of BRD4 antagonist and AC220 or ponatinib against AML BPCs expressing FLT3-ITD, and support the rationale for testing ponatinib and BRD4 antagonist against TKI-refractory AML expressing FLT3-ITD. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The effect of prostaglandins E1 and E2 on macrophage progenitor cells with high proliferative potential in mouse bone marrow in vitro

Blood ◽  
1984 ◽  
Vol 63 (6) ◽  
pp. 1348-1352 ◽  
Author(s):  
AB Kriegler ◽  
TR Bradley ◽  
GS Hodgson
Keyword(s):  
Bone Marrow ◽  
Progenitor Cells ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Synergistic Activity ◽  
Agar Culture ◽  
Inhibition Of Proliferation ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony

Abstract High proliferative potential macrophage progenitor cells (HPP-CFC) in 5- fluorouracil (FU) treated and normal mouse bone marrow (BM) have been shown to be less sensitive to inhibition of proliferation by prostaglandins of the E series (PGE) than low proliferative potential macrophage progenitor cells (LPP-CFC) in normal BM in agar cultures. The growth of large colonies (diameter greater than 0.5 mm) derived from HPP-CFC in FU BM, which require a combination of macrophage colony- stimulating factor (CSF-1) plus a new growth factor called synergistic activity (SA), are inhibited by 50% in the presence of 5.5 X 10(-6) M PGE1. On the other hand, LPP-CFC in normal BM, which form smaller colonies (diameter less than or equal to 0.5 mm) in the presence of CSF- 1 alone, require only 5 X 10(-8) M PGE1 for the same level of inhibition. Addition of appropriate concentrations of PGE1 to the agar culture assay should improve detection of HPP-CFC by inhibiting the proliferation of LPP-CFC. These observations suggest that the apparent negative feedback control of macrophage production by PGE operates largely on the LPP-CFC, which respond to CSF-1 alone, and is probably not involved in the regulation of the more primitive HPP-CFC.

scholarly journals Partial purification and characterization of a growth factor for macrophage progenitor cells with high proliferative potential in mouse bone marrow

Blood ◽  
1982 ◽  
Vol 60 (2) ◽  
pp. 503-508 ◽  
Author(s):  
AB Kriegler ◽  
TR Bradley ◽  
E Januszewicz ◽  
GS Hodgson ◽  
EF Elms
Keyword(s):  
Bone Marrow ◽  
Growth Factor ◽  
Progenitor Cells ◽  
Proteolytic Enzymes ◽  
Partial Purification ◽  
Proliferative Potential ◽  
Mouse Bone Marrow ◽  
Synergistic Activity ◽  
Human Spleen

Abstract A population of macrophage progenitor cells, with high proliferative potential, has recently been demonstrated in postfluorouracil-treated and normal mouse bone marrow (BM) in vitro, when the newly discovered growth factor (synergistic activity, SA) is combined with a macrophage colony-stimulating factor (CSF) as a proliferative stimulus. SA, shown to be present in human spleen and placental conditioned media (HSCM and HPCM, respectively) have been studied and found to be unstable to trypsin digestion and to heating at 50 degrees C or above; stable between pH 4 and 9; nonadherent to Con-A-Sepharose; and to have an isoelectric point between pH 5 and 5.8 and a molecular weight of between 14,000 and 21,000 as indicated by gel filtration chromatography. SAs from both HSCM and HPCM have been purified 89- and 122-fold, respectively, by precipitation of extraneous proteins at pH 5 followed by chromatographing twice on Sephacryl S200. Neither of these partially purified SAs contain any CSF for mouse BM. These results indicate that the SAs from HSCM and HPCM may be closely related and that they are structurally different from CSFs derived from various murine sources that have been shown to be stable to proteolytic enzymes and heat.

scholarly journals Interleukin 13: novel role in direct regulation of proliferation and differentiation of primitive hematopoietic progenitor cells.

1994 ◽  
Vol 180 (1) ◽  
pp. 75-82 ◽  
Author(s):  
S E Jacobsen ◽  
C Okkenhaug ◽  
O P Veiby ◽  
D Caput ◽  
P Ferrara ◽  
...  
Keyword(s):  
Progenitor Cells ◽  
Colony Formation ◽  
Biological Activities ◽  
Hematopoietic Progenitor Cells ◽  
Synergistic Activity ◽  
Hematopoietic Progenitor ◽  
Interleukin 13 ◽  
Gm Csf ◽  
Macrophage Colony

The recently cloned interleukin 13 (IL-13) shares most investigated biological activities on B lymphocytes and monocytes with IL-4. In this study we investigated for the first time the potential role of IL-13 in the regulation of the growth of hematopoietic progenitor cells. IL-13 enhanced stem cell factor (SCF)-induced proliferation of Lin-Sca-1+ bone marrow progenitor cells more potently than IL-4. The effect of IL-13 was purely synergistic, since IL-13 alone stimulated no colony formation. Single cell experiments suggested that the synergistic effect of IL-13 on Lin-Sca-1+ progenitors was directly mediated. In contrast, IL-13 had no synergistic activity on SCF-induced proliferation of the more mature Lin-Sca-1- progenitor cells. Thus, the cloning frequency in response to SCF + IL-13 was at least 20-fold higher in the Lin-Sca-1+ than the Lin-Sca-1- progenitor cell population. Furthermore, IL-13 but not IL-4 synergistically enhanced colony formation of Lin-Sca-1+ progenitors in response to granulocyte/macrophage colony-stimulating factor (GM-CSF) (threefold), whereas both IL-4 and IL-13 enhanced G-CSF-induced colony formation (threefold), and neither of the two significantly affected CSF-1 and IL-3-induced proliferation. Finally, whereas stimulation of Lin-Sca-1+ progenitors by SCF + G-CSF resulted in the formation of 90% granulocytes, the addition of IL-13 resulted in the production of macrophages exclusively. This novel effect on differentiation was directly mediated, shared with IL-4, and could not be observed on Lin-Sca-1- progenitor cells. Collectively, these findings indicate a novel role of IL-13 in early myelopoiesis, partially overlapping but also different from that of IL-4.

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