Investigating the Potential Use of L-Asparaginase in Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3641-3641
Author(s):  
Sung Ah Jun ◽  
Lusia Sepiashvili ◽  
Thomas Kislinger ◽  
Mark D. Minden
Keyword(s):  
Protein Synthesis ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Nuclear Antigen ◽  
Intracellular Enzyme ◽  
Inhibition Of Protein Synthesis ◽  
Factor C ◽  
Resistant Cells

Abstract Abstract 3641 Introduction: L-asparaginase (LA) in combination with other drugs has been one of the standard components of acute lymphocytic leukemia (ALL) therapy for decades. Its antineoplastic effects are likely caused by its depletion of extracellular asparagine and glutamine creating a state of amino acid deficiency and subsequent inhibition of protein synthesis. Despite its efficacy in ALL, LA has been used only occasionally in the treatment of other leukemias and solid tumors. Previous in vitro studies have observed varied response to LA in acute myeloid leukemia (AML) across the French-American-British subtypes. We wanted to elucidate the possible resistance mechanisms of myeloid leukemic cells during LA treatment to increase the efficacy of LA for AML treatment. One of the candidate proteins identified in multiple studies was asparagine synthetase (ASNS), an intracellular enzyme catalyzing the reverse reaction of LA whose expression is up-regulated during nutrient stress. The aim of this study was to investigate the potential of repositioning LA for AML treatment by identifying key components of the cellular response to LA in myeloid leukemic cell lines and primary AML samples. Results: In all the cell lines treated with LA, we observed an inhibition of growth rate and colony formation. Furthermore, we detected apoptotic death by annexin V and propidium iodide staining in most cell lines except for K562. We also observed a leftward shift towards monosomes in polysome profiles of LA sensitive but not insensitive cells, indicating a role for global inhibition of protein synthesis in the effect of LA. To further understand the differences in the responses between resistant and sensitive cell lines at the protein level, we utilized MudPIT (multidimensional protein identification technology) that combines 2-dimensional liquid chromatography coupled to mass spectrometry to separate and identify proteins. Using DAVID, an online program that identifies statistically significant enriched biological themes in gene lists, we compared the MudPIT identified proteomes in LA treated and untreated HL-60 (LA sensitive) and K562 (LA resistant) cells. In HL60, up-regulated proteins in the treated sample were enriched for carbohydrate metabolism (aldolase A, lactate dehydrogenase, 6-phosphogluconolactonase). We also observed decreased expression of proteins involved in cell division (replication factor C, proliferating cell nuclear antigen, minichromosome maintenance complex component 3). The data from K562 is currently being analyzed. A reported predictor of sensitivity to LA is the level of ASNS. To see if this was involved in the resistance of K562 to LA we used shRNA to knockdown ASNS in these cells. While there was some increase in the sensitivity of the cells to LA, the degree of killing did not approach that of other cell lines. Finally, AML primary samples treated with LA were inhibited in their ability to form colonies compared to untreated controls. Interestingly there was no correlation between the level of ASNS and sensitivity of the primary cells. Taken together these studies suggest that other factors are important in mediating the response of cells to LA. Conclusions: Our study shows that LA is effective in killing some forms of AML by inhibiting growth, blocking protein synthesis and inducing apoptosis. Increased sensitivity to LA in ASNS knockdown cell lines indicate a role for ASNS in LA resistance but the absence of strong correlation between ASNS expression and LA resistance in primary samples suggest that ASNS is not solely responsible. The availability of sensitive and resistant myeloid cells provides us with the opportunity to identify mechanisms of resistance. The identification of differentially expressed proteins in the sensitive and resistant cells using MudPIT will help to identify targets that if blocked can synergize with LA and render a resistant cell sensitive. Disclosures: Off Label Use: L-asparaginase is a drug used to treat acute lymphocytic leukemia.

Activities and Mechanism Based Combinations Of Omacetaxine In Acute Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1288-1288
Author(s):  
Rong Chen ◽  
Bonnie Leung ◽  
Yuling Chen ◽  
William Plunkett
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Synthesis ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Bh3 Mimetics ◽  
Abl Kinase ◽  
Acute Myeloid

Abstract Omacetaxine, an inhibitor of translation, was recently granted accelerated approval for the treatment of chronic myeloid leukemia (CML). Omacetaxine blocks translation elongation by competing with the incoming aminoacyl-tRNAs for binding to the A-site cleft in the peptidyl-transferase center. Our previous studies showed that by transiently inhibiting translation, omacetaxine reduced the expression of the key, short-lived oncoproteins Bcr/Abl and Mcl-1, leading to cell death in the CML cells. This action sensitized the cells to the Abl kinase inhibitor and killed the CML cells synergistically. Further, as omacetaxine acts in a different mechanism than the Abl kinase inhibitors, it overcame resistance to TKI that was associated with kinase domain mutations. These studies paved the foundation for the clinical development of omacetaxine in CML. We also demonstrated that omacetaxine was active in chronic lymphocytic leukemia by translational inhibition of Mcl-1 expression. In contrast to normal tissues, the fact that the leukemia cells are critically dependent on the oncogene activity for survival provided a biologic context for a positive therapeutic index. As the biological features of acute myeloid leukemia (AML) rely largely on the overexpressed oncoproteins or constitutively activated kinases, we hypothesized that omacetaxine would have therapeutic benefit in AML either alone or in mechanism based combinations. To test this hypothesis, first, we compared omacetaxine to AC220, a potent FLT3 inhibitor, in AML cell lines OCI-AML3 and MV4-11. OCI-AML3 cells harbor the signature mutation of NPM1, whereas MV4-11 is a widely used model for the internal tandem duplications of FLT3 (FLT3-ITD), a common FLT3 mutation that constitutively activates the receptor tyrosine kinase. AC220 was selectively toxic to the MV4-11 cells, but had no effect on the viability of OCI-AML3. This is consistent with the biological context of MV4-11, but not OCI-AML3, that is addicted to the sustained activity of FLT3 for survival. In contrast, omacetaxine induced apoptosis in both cell lines with IC50s less than 100 nM. Protein synthesis was inhibited in both lines, measured by the incorporation of tritiated leucine. Apoptosis was induced rapidly within 24 h by omacetaxine, whereas AC220 required 72 h to kill the leukemia cells. These results indicated a common dependence on the continued protein synthesis in the AML lines, suggesting a potentially broad application of omacetaxine in AML patients with diverse genetic backgrounds. Over-expression of the anti-apoptotic protein Mcl-1 is associated with AML disease maintenance and resistant to therapy. Both Mcl-1 and FLT3 turn-over rapidly and are vulnerable targets of transient translation inhibition. Immunoblots showed that omacetaxine reduced the levels of both FLT3 and Mcl-1 in the MV4-11 cells. This activity augmented the effect of AC220 on FLT3 kinase, and induced synergistic apoptosis. Same synergistic combination was observed with omacetaxine and sunitinib, an inhibitor of FLT3, KIT and PDGF-R. Dose reduction index derived from these analyses showed that omacetaxine greatly potentiated the activity of both AC220 and sunitinib, resulting in profound apoptosis. Both Bcl-2 and Mcl-1 are pro-survival proteins that regulate apoptosis by interacting with the BH3 motifs of their pro-apoptotic partners. BH3 mimetics, such as ABT-199, bind with high affinity to Bcl-2 and block this interaction, but not to Mcl-1. Resistance to BH3 mimetics in AML cells is associated with upregulation of Mcl-1. Since ABT-199 inhibits Bcl-2 but spares Mcl-1, and omacetaxine reduces Mcl-1 without affecting Bcl-2 expression, we hypothesized that their combination would target the two parallel arms of apoptosis control and kill the AML cells synergistically. Indeed, omacetaxine reduced Mcl-1 in the OCI-AML3 cells, leading to loss of mitochondrial membrane potential and apoptosis. ABT-199 blocked Bcl-2 function and also induced the intrinsic pathway of apoptosis. Their combination induced greater mitochondrial damage and apoptosis than either drug alone. The median effect analysis showed that they potentiate each other and exhibited strong synergy. Taken together, these results demonstrated that omacetaxine is active in AML cells alone and in mechanism based combinations. These actions provide rationale that warrants investigation in the clinic. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Cytotoxicity Assessment and Apoptosis-related Gene Profiling of Antibody Treated Acute Myeloid Leukemia (AML) and Acute Lymphocytic Leukemia (ALL) Cancerous Cell Lines

2020 ◽  
Author(s):  
Mahdi Habibi-Anbouhi ◽  
Zahra Kafi ◽  
Leila Ghazizadeh ◽  
Shabnam Kharazi ◽  
Mahdi Behdani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Monoclonal Antibodies ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Surface Markers ◽  
Hematopoietic Stem ◽  
Cancerous Cell ◽  
Acute Myeloid

Acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL) are common acute leukemia in adults and children, respectively. In these malignancies, chemotherapy is the main treatment strategy that fails in many cases and is usually associated with adverse effects on healthy cells. In this regard, the development of new therapies is essential. Monoclonal antibodies directed to the cell surface markers of leukemic blasts may have promising consequences with minimal toxic effects on normal cells. Since cluster of differentiation 45Ra (CD45Ra) and CD123 antigens, two considered surface markers of leukemic blasts in AML and ALL respectively, are overexpressed on AML and ALL blasts, CD34+ leukemic progenitors, and AML-LSCs in comparison with normal hematopoietic stem cells (HSCs), they were selected to be targeted; using specific monoclonal antibodies. In this project, CD45Ra+ cells and CD123+ cells were targeted by anti-CD45Ra and/or anti-CD123 monoclonal antibodies. Cytotoxicity effect and cell death induction was determined by 3-(4,5-dimethylthiazol-2-yl)-2–5-diphenyltetrazolium bromide (MTT) assay and flow cytometry. Changes in the expression profile of MCL1, cMyc, Survivin, Id1, and PIM1 genes were assessed by real-time PCR. Statistical analysis of the results showed effective antibody-mediated cytotoxicity and induction of apoptosis in KG1α (CD45Ra+) and Nalm6 (CD123+) cell lines. Also, a significant change in the expression level of some of the apoptosis-related genes was observed. According to the results of this study, it can be concluded that an effective targeting of AML and ALL cancerous cell lines can be performed by anti-CD45Ra and anti-CD123 monoclonal antibodies through their effector functions and apoptosis induction.

scholarly journals Influence of cytotoxicity enhancers in combination with human serum on the activity of CD22-recombinant ricin A against B cell lines, chronic and acute lymphocytic leukemia cells

Leukemia ◽  
1999 ◽  
Vol 13 (2) ◽  
pp. 241-249 ◽  
Author(s):  
PJ van Horssen ◽  
YVJM van Oosterhout ◽  
S Evers ◽  
HHJ Backus ◽  
MGCT van Oijen ◽  
...  
Keyword(s):  
B Cell ◽  
Human Serum ◽  
Cell Lines ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Leukemia Cells ◽  
Ricin A

scholarly journals Bacterial Ribonuclease MazF-Mediated Apoptosis as Potential Cancer Therapy

2021 ◽  
Author(s):  
Maryam Saffarian Abbas Zadeh ◽  
Rebecca Anne MacPherson ◽  
Guohui Huang ◽  
Hui Ding ◽  
Rhonda Reigers Powell ◽  
...  
Keyword(s):  
Cell Death ◽  
Protein Synthesis ◽  
Cell Lines ◽  
Mrna Translation ◽  
Protein Translation ◽  
Programmed Death ◽  
Inhibition Of Protein Synthesis ◽  
Cancer Agent ◽  
Cell Suicide ◽  
The Impact

Abstract Programmed cell death is a dynamic and critical mechanism of cell suicide in eukaryotes and prokaryotes. MazF is a ribonuclease protein involved in bacterial intracellular programmed death. This protein cleaves mRNAs at ACA sequences, leading to inhibition of protein synthesis and triggering cell death. Given that cancer is heterogenic and has varied susceptibility to treatment, we examined the impact of MazF proteins on the growth and viability of three cancer cell lines: MCF7, HT29, and AGS. These cell lines were transfected with ACA-less mazF mRNAs and evaluated for MazF-mediated cell death. The data illustrated that efficient MazF translation leads to a significant reduction in cell viability and is modulated by structural elements of ACA-less mazF mRNAs. In the presence of MazF, the levels of activated caspase-3 and -7 were significantly elevated in transfected cells, confirming the occurrence of apoptosis. We also quantified mRNA translation on a single-cell basis in MCF7 and AGS cell lines to examine MazF-mediated inhibition of protein synthesis. MazF expression significant decreases the levels of protein translation in the examined cell lines. This is the first report of MazF as a potential anti-cancer agent via induction of apoptosis in MCF7, AGS, and HT-29 cell lines.

scholarly journals Mesenchymal Stem Cells (MSCs) Intensify the Impact of KIR Ligand-Mismatching on Acute Graft-Versus-Host Disease Post HSCT in Patients with Acute Myeloid Leukemia but Not with Acute Lymphocytic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-42
Author(s):  
Yu Zhang ◽  
Shaozhen Chen ◽  
Jinhua Ren ◽  
Xiaofeng Luo ◽  
Zhizhe Chen ◽  
...  
Keyword(s):  
Stem Cells ◽  
Acute Myeloid Leukemia ◽  
Mesenchymal Stem Cells ◽  
Graft Versus Host Disease ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Graft Versus Host ◽  
Gvhd Prophylaxis ◽  
Acute Myeloid

Objectives: Mesenchymal stem cells (MSCs) and killer cell immunoglobulin-like receptor (KIR) ligand-mismatch, which can trigger the alloreactivity of natural killer (NK) cells, have been shown to be protective for severe acute and chronic graft-versus-host disease (aGVHD, cGVHD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there are no prospective or retrospective studies exploring their relationship. Here, we investigated the potential influence of KIR matching, MSCs and their coaction on GVHD prophylaxis, overall survival (OS) and relapse rate (RR) of allo-HSCT. Methods: Data from 154 patients with acute myeloid and lymphocytic leukemia treated with allo-HSCT between May 2015 and May 2020 in the transplantation unit of the Fujian Medical University Union Hospital were retrospectively analyzed. The cohort included 93 male patients (60.3%) and 61 female (39.7%), with a median age of 24 years (1-59 years), 104 cases of acute myeloid leukemia (AML; 67.5%) and 50 cases with acute lymphocytic leukemia (ALL; 32.5%). Eighty-one patients (52.6%) underwent MSCs infusion on day+1. The sources of MSCs were human placenta or human bone marrow. MSCs infusion dose ranged from 0.5 to 3x106/kg of recipient weight. KIR genotyping was performed by the PCR-SSO method. The amplicons were quantified on the Luminex 200 flow analyzer and analyzed using the Quick-Type for Lifecodes software for generating KIR data. Cox proportional hazards model and Kaplan-Meier survival curves were used for analysis. Results: At the time of transplantation, 65 cases (42.2%) were in remission, while 89 (57.8%) had active disease. aGVHD occurred in 31 patients (20.1%) and recurrence arose in 21 patients (13.6%), but no significant cGVHD was observed. After adjusting for age, disease-risk, HLA-match, donor gender, conditioning regimen intensity and type of post-grafting GVHD prophylaxis, Cox regression analysis revealed that KIR ligand-matching was associated with an increased risk of aGVHD compared to KIR ligand-mismatching (p=0.023) in AML patients, but KIR ligand-mismatching had no significant effect on aGVHD in ALL patients, and on OS and RR in both AML and ALL patients. MSCs was associated with much lower recurrence rate (RR) (p=0.049), even when the recipients were not in remission at the time of HSCT. Furthermore, MSCs reduced the incidence of aGVHD in both AML and ALL patients, although it did not reach statistical significance (p=0.19). The combination of KIR ligand-mismatching and MSCs infusion significantly suppressed aGVHD occurrence in AML patients (p=0.033). More importantly, MSCs infusion intensified the suppression effect of KIR ligand-mismatching on aGVHD in AML patients (p=0.047). In the KIR ligand-mismatch group, the incidence of aGVHD was 10.3% when patients received MSCs, compared to 25.6% in those who did not. However, combining KIR ligand-mismatch and MSCs injection had no significant effect on aGVHD in ALL patients, or on OS and RR in both AML and ALL patients. Conclusions: KIR ligand-mismatch, MSCs infusion and their combination significantly reduced the risk of aGVHD after allo-HSCT in AML patients. It confirms the relationship between MSCs injection and lower RR. These data provide a clinically applicable strategy where co-transplantation with MSCs and triggering of allo-NK cells by KIR ligand-mismatching can ameliorate aGVHD, thus improving allo-HSCT outcome in AML patients. Disclosures No relevant conflicts of interest to declare.

Inhibition of protein synthesis and heat protection: Histidinol-resistant mutant cell lines

1991 ◽  
Vol 149 (3) ◽  
pp. 396-402 ◽  
Author(s):  
Yong J. Lee ◽  
Zi-Zheng Hou ◽  
Dooha Kim ◽  
Abdul Al-Saadi ◽  
Peter M. Corry
Keyword(s):  
Protein Synthesis ◽  
Cell Lines ◽  
Mutant Cell ◽  
Resistant Mutant ◽  
Heat Protection ◽  
Inhibition Of Protein Synthesis

Repositioning of Quinacrine for Treatment of Acute Myeloid Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3609-3609
Author(s):  
Anna Eriksson ◽  
Albin Osterros ◽  
Sadia Hassan ◽  
Joachim Gullbo ◽  
Linda Rickardson ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
Cytotoxic Activity ◽  
Tumor Cells ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Lymphocytic Leukemia ◽  
Ribosomal Biogenesis ◽  
Rheumatic Drug ◽  
Acute Myeloid

Abstract Background: A promising strategy for new drug discovery is ‘repositioning’, in which a new indication for an existing drug is identified. Using this approach, known on-patent, off-patent, discontinued and withdrawn drugs with unrecognized cancer activity, can be rapidly advanced into clinical trials for the new indication. We here report findings from a library screen of pharmacologically active and mechanistically annotated compounds in leukemia cells from patients aiming at the identification of repositioning candidates. Methods and results: The LOPAC®, 1280substance library (Sigma-Aldrich), with 1266 mechanistically annotated compounds, were investigated for cytotoxic activity by the fluorometric microculture cytotoxicity assay (FMCA) on tumor cells from 12 patients with leukemia (4 acute lymphocytic leukemia, 4 acute myeloid leukemia [AML], 4 chronic lymphocytic leukemia), as well as on peripheral blood mononuclear cells (PBMC) from 4 healthy donors. Sixty-eight compounds were identified as hits, defined as having a cytotoxic activity (less than 50% cell survival compared with controls) in all leukemia subgroups at the 10µM drug concentration used for screening. Only one of the hit compounds, quinacrine, showed higher activity in the leukemic cells than in normal PBMCs and was therefore selected for further preclinical evaluation focusing on AML. The aminoacridine quinacrine has a wide range of biological and therapeutical applications, and has been used for decades outside hemato-oncology, notably as an anti-protozoal and anti-rheumatic drug. Its side effects and toxicity are well characterized. Quinacrine showed significant cytotoxic activity in all four AML cell lines tested (HL-60, Kasumi-1, KG1a and MV4-11). In tumor cells from another 9 patients with AML, the cytotoxic effect (IC50 median 1.8, range 0.8-4 µM) was significantly superior to that in normal lymphocytes and clearly dose-dependent. Analysis of quinacrine data from the National Cancer Institute growth inhibitory screen in 60 cell lines (NCI 60 GI 50 data) was performed with the help of the NCI Cellminer database (http://discover.nci.nih.gov/cellminer/), and indicated leukemia sensitivity. To examine the ability of quinacrine to reverse diagnosis-specific gene expression, we utilized the Nextbio bioinformatics software, with its gene expression signatures of drug exposed myeloid leukemia cell cultures (HL60). These queries showed that myeloid leukemias had high reversibility scores. Moreover, gene enrichment and drug correlation data revealed a strong association to ribosomal biogenesis nucleoli. Translation initiation was observed including a high drug-drug correlation with ellipticine, a known inhibitor of RNA polymerase I (Pol-I). To validate the latter results, gene expression analysis of HL-60 cells exposed to quinacrine were obtained using the protocol described by Lamb et al (Science, 2006, 313, 1929), showing down regulation of Pol-1 associated RNA. Supporting these findings, quinacrine induced early inhibition of protein synthesis. Conclusions: The anti-protozoal and anti-rheumatic drug quinacrine has significant in vitro activity in AML. The anti-leukemic effect may be mediated by targeting ribosomal biogenesis. Considering its favorable and well-known safety profile, clinical studies of quinacrine in AML should be considered. Disclosures No relevant conflicts of interest to declare.

The BTK Inhibitor Ibrutinib Blocks SDF1/CXCR4 Mediated Migration of Acute Myeloid Leukemia Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 915-915
Author(s):  
Stuart A Rushworth ◽  
Lyubov Zaitseva ◽  
Megan Y Murray ◽  
Matthew J Lawes ◽  
David J MacEwan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Lymphocytic Leukemia ◽  
Cell Trafficking ◽  
Acute Myeloid

Abstract Introduction Despite recent significant progress in the understanding of the biology of acute myeloid leukemia (AML) the clinical outcomes for the majority of patients diagnosed with AML presently remain poor. Consequently, there is an urgent need to identify pharmacological strategies in AML, which are not only effective but can be tolerated by the older, less well patient. Recently our group and others have shown that there is high Bruton’s Tyrosine Kinase (BTK) phosphorylation and RNA expression in AML. Moreover, our recent study described for the first time that ibrutinib and BTK-targeted RNA interference reduced factor-induced proliferation of both AML cell lines and primary AML blasts, as well as reducing AML blast adhesion to bone marrow stromal cells. Inhibition of BTK has been shown to regulate chronic lymphocytic leukemia, mantle cell lymphoma and multiple myeloma cell migration by inhibiting SDF1 (stromal derived factor 1) induced CXCR4 regulated cell trafficking. Here we report that in human AML ibrutinib in addition functions in a similar way to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. Methods To investigate the role of BTK in regulating AML migration we used both pharmacological inhibitor ibrutinib and genetic knockdown using a lentivirus mediated BTK targeted miRNA in primary AML blasts and AML cell lines. We examined migration of AML blasts and AML cells to SDF-1 using Transwell permeable plates with 8.0µM pores. Western blotting was used to examine the role of SDF-1 in regulating BTK, AKT and MAPK activation in primary AML blasts. Results We initially examined the expression of CXCR4 in human AML cell lines and found that 4/4 cell lines were positive for CXCR4 expression. Next we examined the effects of ibrutinib on the migration of the AML cell lines U937, MV4-11, HL60 and THP-1 in response to SDF1. We found that ibrutinib can inhibit the migration of all AML cell lines tested. We tested the in-vitro activity of ibrutinib on SDF-1 induced migration in a spectrum of primary AML blasts from a wide age spectrum of adult patients and across a range of WHO AML subclasses and found that ibrutinib significantly inhibits primary AML blast migration (n=12). Next we found that ibrutinib can inhibit SDF-1 induced BTK phosphorylation and downstream MAPK and AKT signalling in primary AML blast. Finally to eliminate the problems associated with off target ibrutinib activity we evaluated migration of AML cells lines using genetic inhibition of BTK. The introduction of BTK-specific miRNA dramatically inhibited the expression of BTK in THP-1 and HL60 and reduced SDF1 mediated migration confirming that BTK is involved in regulating AML migration in response to SDF1. Conclusions These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL. Disclosures No relevant conflicts of interest to declare.

Proptosis as Initial Presentation of Acute Lymphoblastic Leukemia in a Child with no associated symptoms: A Case Report

2020 ◽  
Author(s):  
Kourosh Goudarzipour ◽  
Ahmad Mohammadi ◽  
Reza Taherian ◽  
Mehran Arab Ahmadi ◽  
Behdad Behnam ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myeloid Leukemia ◽  
Acute Lymphocytic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Rapid Diagnosis ◽  
Lymphocytic Leukemia ◽  
Initial Presentation ◽  
Associated Symptoms ◽  
Blast Cells

Acute lymphocytic leukemia (ALL) is one of the frequent malignancies in pediatrics and involves bone marrow and extramedullary sites. Proptosis as extramedullary involvement of leukemia usually present in acute and chronic myeloid leukemia. It is extremely rare for ALL to present initially as proptosis.Here, a-21-month-old boy was presented with proptosis without any associated symptoms except lymphadenopathy. He was referred with the impression of malignancy from an ophthalmologist. After bone marrow biopsy which showed 33% blast cells, all positive for CD10, CD19, and CD79, the diagnosis of pre-B cell ALL was finally made. His symptoms were improved completely 16 days after starting standard protocol for ALL.Afterone-year follow-up, he was free of any symptoms.According to this initial presentation of ALL and no typical associated symptoms, it is important to make rapid diagnosis and start the treatment in the childhood.

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