scholarly journals Prognostic Impact of Flow Cytometric Measurement of G Protein–Coupled Receptor 56 (GPR56) in Acute Myeloid Leukemia

2021 ◽  
Vol 85 (1) ◽  
pp. 2788-2793
Author(s):  
Hanaa M. Sayed Afifi ◽  
Mai A. Rashad ◽  
Haitham M. Abdelbary ◽  
Rasha A. El-Gamal
Keyword(s):  
Acute Myeloid Leukemia ◽  
G Protein ◽  
Myeloid Leukemia ◽  
Prognostic Impact ◽  
G Protein Coupled Receptor ◽  
Flow Cytometric ◽  
Flow Cytometric Measurement ◽  
G Protein Coupled ◽  
Acute Myeloid

scholarly journals Expression of G Protein–Coupled Receptor 56 (GPR56) in Acute Myeloid Leukemia

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
H M S Afifi ◽  
R A Elgamal ◽  
H M Abdelbary ◽  
M A Rashad
Keyword(s):  
Acute Myeloid Leukemia ◽  
G Protein ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Prognostic Impact ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous marrow-based clonal group of neoplasms that affects hematopoietic cells responsible for the production of myeloid lineages. Prognosis of AML is multifactorial and has been extensively studied, yet it’s highly dependent on the presence of leukemic stem cells (LSCs). G protein–coupled receptor 56 (GPR56) was introduced as a novel human LSC marker in AML patients as acknowledged by the engraftment potential of GPR56+ cells sorted from selected AML specimens, which contributed to leukemia propagation in mice. Aim of the work The aim of this study is to analyze GPR56 expression in de novo AML patients using flow cytometry. The results of GPR56 expression will be correlated with the clinical outcome of the patients as well as other laboratory parameters. Subjects and Methods The study was carried out at Ain Shams University hospitals on a total number of 40 AML patients attending hematology-oncology unit during the period from November 2016 to July 2017, in addition to 20 healthy control subjects. Patients were assessed at day 28 after induction of treatment by bone marrow examination and minimal residual disease analysis, and follow up of the disease course was done. Results GPR56 was highly expressed above mean in 62.5% of AML patients. High values were significantly related to failure to attain complete remission, whereas it lacked prognostic significance to patient outcome and cytogenetic subgroups. Conclusion The poor prognostic impact of GPR56 was partially validated in our study. Recommendations Flow cytometric evaluation of GPR56 should be incorporated into the initial laboratory work-up for all newly diagnosed AML patients.

scholarly journals Imipridone ONC212 activates orphan G protein-coupled receptor GPR132 and integrated stress response in acute myeloid leukemia

Leukemia ◽  
2019 ◽  
Vol 33 (12) ◽  
pp. 2805-2816 ◽  
Author(s):  
Takenobu Nii ◽  
Varun V. Prabhu ◽  
Vivian Ruvolo ◽  
Neel Madhukar ◽  
Ran Zhao ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Stress Response ◽  
G Protein ◽  
Myeloid Leukemia ◽  
Integrated Stress Response ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled ◽  
Acute Myeloid

scholarly journals Clonal Heterogeneity Reflected by PI3K-AKT-mTOR Signaling in Human Acute Myeloid Leukemia Cells and Its Association with Adverse Prognosis

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 332 ◽  
Author(s):  
Ina Nepstad ◽  
Kimberley Joanne Hatfield ◽  
Tor Henrik Anderson Tvedt ◽  
Håkon Reikvam ◽  
Øystein Bruserud
Keyword(s):  
Gene Expression ◽  
Acute Myeloid Leukemia ◽  
G Protein ◽  
Myeloid Leukemia ◽  
Expression Profiles ◽  
Mtor Pathway ◽  
Prognostic Impact ◽  
Clonal Heterogeneity ◽  
G Protein Coupled ◽  
Acute Myeloid

Clonal heterogeneity detected by karyotyping is a biomarker associated with adverse prognosis in acute myeloid leukemia (AML). Constitutive activation of the phosphatidylinositol-3-kinase-Akt-mechanistic target of rapamycin (PI3K-Akt-mTOR) pathway is present in AML cells, and this pathway integrates signaling from several upstream receptors/mediators. We suggest that this pathway reflects biologically important clonal heterogeneity. We investigated constitutive PI3K-Akt-mTOR pathway activation in primary human AML cells derived from 114 patients, together with 18 pathway mediators. The cohort included patients with normal karyotype or single karyotype abnormalities and with an expected heterogeneity of molecular genetic abnormalities. Clonal heterogeneity reflected as pathway mediator heterogeneity was detected for 49 patients. Global gene expression profiles of AML cell populations with and without clonal heterogeneity differed with regard to expression of ectopic olfactory receptors (a subset of G-protein coupled receptors) and proteins involved in G-protein coupled receptor signaling. Finally, the presence of clonal heterogeneity was associated with adverse prognosis for patients receiving intensive antileukemic treatment. The clonal heterogeneity as reflected in the activation status of selected mediators in the PI3K-Akt-mTOR pathway was associated with a different gene expression profile and had an independent prognostic impact. Biological heterogeneity reflected in the intracellular signaling status should be further investigated as a prognostic biomarker in human AML.

Prognostic Impact of Pretransplantation Minimal Residual Disease Detection for Flow Cytometric, on Outcome of Allogeneic Hematopoietic Cell Transplantation for Acute Myeloid Leukemia. a Single Center Experience in Colombia over 14 Years

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5411-5411
Author(s):  
Andres Armando Borda Molina ◽  
Iris Cordoba ◽  
Virginia Abello ◽  
Carmen Rosales ◽  
Rosales Manuel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Minimal Residual Disease ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Prognostic Impact ◽  
Allogeneic Bone ◽  
Flow Cytometric ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background: The accumulated evidence from studies of multiparameter flow cytometric MRD (MFC-MRD) assessment in AML leaves little doubt that this method of MRD detection can be used to risk stratify both younger and older patients at treatment time points. Persistence of disease or high levels of pretransplantation minimal residual disease (MRD) have been reported to predict disease relapse after Allogeneic bone marrow transplantation (BMT). The prognostic impact of MFC-MRD is strong enough to have emerged despite study differences in the MFC assays and the limitations of now outdated restricted antibody panels. Aims: To determine the value of Minimal Residual Disease (MRD) assessed by Multi-parameter Flow Cytometry (MFC) pretransplantation Allogeneic BMT, in predicting outcome in patients with acute myeloid leukemia (AML). Methods: We performed a retrospective analysis the predictive value of MRD assessment by MFC pre trasnplantation alogeneic in 119 patients (diagnosed AML treated between january 2010 and october 2014 submitted at our institution who had available MRD assessment). MRD by MFC on bone marrow specimens obtained approximately 30 days before transplantation. MRD was identified as a cell population showing deviation from normal antigen expression patters compared with normal or regenerating marrow. The detection threshold for defining pre transplantation positive MRD was >0.3%. Results - Of the 119 patients, 80 (67%) were in complete remission (CR1) , 31 (26%) CR2 and > CR2 8 (6%). Their median age was 38 years (Range, 10-64). Hyperleucocytosis in 39 (32%) and Cytogenetics was favorable risk in 32 (26%), intermediate risk in 39 (32.%), adverse risk in 35 (29%) and unknown in 13 (14%). There were a total of 44 deaths and 17 relapses; these contributed to the probability estimates for overall survival (OS) and disease free survival (DFS), stratified by MRD status and shown in figure 1. The median follow-up after BMT among survivors was 8.3 years (range, 6.9 to 9,6 years). The 7.5-years estimates of OS for MRD-positive and MRD-negative patients were 43.1% (range, 23,2% to 58,6%) and 68% (range 56% to 78.3%), respectively, and the 7,5 year estimates for DFS for MRD-positive and MRD-negative patients were 40.5% (range 21.4% to 52.6%) and 56% (range 42.5% to 65.8%). After adjustment for various covariates, age, cytogenetics risk, hyperleucocytosis, secundary AML, the hazard ratios of MRD positive versus MRD negative were 2.06 (range 1.52 to 6.24; P=0,003) for overall mortality, 3.45 ( range 2.14 to 7.32; p=0.014) for DFS. Conclusion: That detection of MRD pre transplantation define a population of patients with AML who are at higher risk for adverse outcome, even after adjusting for other factors that influence post-BMT outcome. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals An Overview on G Protein-coupled Receptor-induced Signal Transduction in Acute Myeloid Leukemia

2019 ◽  
Vol 26 (28) ◽  
pp. 5293-5316 ◽  
Author(s):  
Frode Selheim ◽  
Elise Aasebø ◽  
Catalina Ribas ◽  
Anna M. Aragay
Keyword(s):  
Acute Myeloid Leukemia ◽  
G Protein ◽  
Myeloid Leukemia ◽  
Protein Profiling ◽  
Bibliographic Databases ◽  
Term Survival ◽  
Gpcr Signaling ◽  
Clinical Biomarkers ◽  
G Protein Coupled ◽  
Acute Myeloid

Background: Acute Myeloid Leukemia (AML) is a genetically heterogeneous disease characterized by uncontrolled proliferation of precursor myeloid-lineage cells in the bone marrow. AML is also characterized by patients with poor long-term survival outcomes due to relapse. Many efforts have been made to understand the biological heterogeneity of AML and the challenges to develop new therapies are therefore enormous. G Protein-coupled Receptors (GPCRs) are a large attractive drug-targeted family of transmembrane proteins, and aberrant GPCR expression and GPCR-mediated signaling have been implicated in leukemogenesis of AML. This review aims to identify the molecular players of GPCR signaling, focusing on the hematopoietic system, which are involved in AML to help developing novel drug targets and therapeutic strategies. Methods: We undertook an exhaustive and structured search of bibliographic databases for research focusing on GPCR, GPCR signaling and expression in AML. Results and Conclusion: Many scientific reports were found with compelling evidence for the involvement of aberrant GPCR expression and perturbed GPCR-mediated signaling in the development of AML. The comprehensive analysis of GPCR in AML provides potential clinical biomarkers for prognostication, disease monitoring and therapeutic guidance. It will also help to provide marker panels for monitoring in AML. We conclude that GPCR-mediated signaling is contributing to leukemogenesis of AML, and postulate that mass spectrometrybased protein profiling of primary AML cells will accelerate the discovery of potential GPCR related biomarkers for AML.

The G Protein-Coupled Receptor cysLT1 Is Expressed in Acute Myeloid Leukemia Mediating Cell Migration and Survival.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1933-1933
Author(s):  
Christina Rether ◽  
Sandra Hengstebeck ◽  
Xingkui Xue ◽  
Andreas Boehmler ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Cell Migration ◽  
G Protein ◽  
Myeloid Leukemia ◽  
Leukemic Cell ◽  
Dependent Manner ◽  
G Protein Coupled ◽  
Dose Dependent ◽  
Acute Myeloid

Abstract Previous studies have shown that the G protein-coupled receptor (GPCR) cysLT1, which recognizes inflammatory lipid mediators (cysteinyl-leukotrienes), is expressed in immature hematopoietic and tumor (eg. colon cancer) cells. In the present study, we analyzed leukemic blasts from 19 patients with newly diagnosed acute myeloid leukemia for analysis of expression and function of cysLT1. By RT-PCR, cysLT1 mRNA was found in all primary AML cells. Quantitative TaqMan PCR demonstrated high levels particularly in acute myeloblastic leukemia without maturation (FAB M1). There was also a positive correlation between the cysLT1 mRNA level and the expression of CD34 and CD-117 (c-kit), indicating that high cysLT1 expression corresponds to an AML phenotype resembling normal hematopoietic progenitor cells. CysLT1 was functionally active in AML blasts, as demonstrated by intracellular calcium fluxes and actin polymerization induced by the ligand LTD4. Similar to mRNA expression, strongest responses were seen in AML FAB M1. As LTD4 can be produced in the bone marrow by stromal cells and may contribute to bone marrow infiltration of AML, chemotaxis was analyzed. Surprisingly, already low concentrations (10nM) induced significant chemotaxis of AML blasts, while higher concentrations (up to 1 uM) were less effective in a dose-dependent manner. Incubation of myeloid leukemic cell lines (eg. KG1a) and primary AML blasts with the specific cysLT1 antagonist MK571 resulted in significantly reduced viability after 48 h in a dose-dependent manner (10nM-10uM), suggesting also an autocrine function of cysLT1 ligands. To explore signal transduction pathways involved in leukemic cell proliferation and chemotaxis, we found that in AML cell lines, LTD4 induced phosphorylation of Erk/MAP kinase, wich is related to proliferation, and Pyk2, which represents a focal adhesion kinase-like signaling molecule that links GPCRs with cell migration, while the Akt pathway was not involved. We conclude that cysLT1 is consistently expressed in acute myeloid leukemia, and mediates both chemotactic and proliferative responses. Therefore, cysLT1 antagonists, which are already used in the treatment of allergy, may improve the effectiveness of antileukemic therapy.

Transcriptome Analysis Reveals That G Protein-Coupled Receptors Are Potential Diagnostic Markers or Therapeutic Targets in Acute Myeloid Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3855-3855 ◽  
Author(s):  
Arhamatoulaye Maiga ◽  
Sébastien Lemieux ◽  
Caroline Pabst ◽  
Vincent-Philippe Lavallée ◽  
Michel Bouvier ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
G Protein ◽  
Transcriptome Analysis ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Therapeutic Targets ◽  
G Protein Coupled Receptors ◽  
Differentially Expressed ◽  
G Protein Coupled ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is associated with poor overall survival and the development of more effective therapies is urgently needed. G Protein-Coupled Receptors (GPCRs) represent the largest family of membrane receptors, with an estimated 800 members in humans, and are attractive therapeutic targets, accounting for approximately 30% of targets of marketed drugs. These receptors are key transducers that bind a vast diversity of ligands (e.g. glycoproteins, peptides, amino acids, nucleotides, nucleosides, ions) allowing the cells to adapt to their environment by regulating a wide variety of physiological processes including the control of blood pressure, heart rate, digestive processes, hormone secretion, cell growth and migration, as well as vision and olfaction. Binding to their ligands leads to conformational rearrangements promoting the engagement and modulation of many distinct downstream signaling effectors that are both G protein-dependent and independent. Several GPCRs are critical for cell proliferation and survival, and can be aberrantly expressed in cancer cells. For example, the chemokine receptor CXCR4 plays an important role in metastasis and angiogenesis in breast cancer and many other types of tumors. In AML, CXCR4 overexpression has been associated with poor outcome. Moreover, in vivo mouse studies have shown that the use of a small molecule antagonist of CXCR4 increases the mobilization of AML cells into the peripheral blood and improves the apoptotic effects of chemotherapy. This activity has been explored in a phase I/II clinical study showing that the addition of CXCR4 antagonists to chemotherapy in AML might improve the remission rate. The role of GPCRs in mouse leukemogenesis has also been suggested in a transcriptome analysis of two related leukemia clones that differ in their stem cell frequency. In this study, GPCRs were the most differentially expressed class of genes between the two clones. Currently, an extensive assessment of GPCR expression in human AML is lacking. To address this issue, we studied the expression of GPCRs in a large cohort of AML samples, as well as in normal blood cells, bone marrow cell populations, and cord blood-derived CD34+ cells as controls.The 772 GPCRs analyzed in this study consist of all the GPCR members included in the International Union of Basic and Clinical Pharmacology (IUPHAR) database, as well as 370 olfactory, 24 taste and 4 vomeronasal receptors. RNA sequencing data analysis was performed as previously described (Lavallée et al, Blood 2015 Jan 1;125(1):140-3) and revealed that 240 GPCRs are expressed in cells from this AML cohort. Among these receptors, 30 are upregulated and 19 are downregulated in AML samples compared to CD34+ normal cells. Upregulated GPCRs are enriched in chemokine (CCR1, CXCR4, CCR2, CX3CR1, CCR7, and CCRL2), adhesion (CD97, EMR1, EMR2, and GPR114) and purine (including P2RY2 and P2RY13) receptor sub-families. The downregulated members include adhesion GPCRs such as LPHN1, GPR125, GPR56, CELSR3, and GPR126, protease-activated receptors (F2R and F2RL1), and the Frizzled family receptors SMO and FZD6. Interestingly, specific deregulation was observed in genetically distinct subgroups of AML, a subset of GPCRs being differentially expressed in normal karyotype AML with NPM1 or FLT3 -ITD mutations, and in specimens with Core Binding Factor and MLL rearrangements, thereby representing promising therapeutic targets or diagnostic markers. In conclusion, our results demonstrate that several GPCR members are deregulated in AML with a clear enrichment in distinct classes, providing the rationale for functional assays using available agonists or antagonists to leukemia-enriched GPCRs. Since these receptors are the targets of several US Federal and Drug Administration approved drugs, our results pave the way to explore selected GPCRs as novel AML therapeutic targets. Disclosures Bouvier: American Society of Nephrology: Other: speaker; Domain Therapeutics: Other: Company SAB member, Research Funding; Vertex Pharmaceutical: Research Funding; Ontario Genomic Institute: Other: SAB meeting; BMS: Research Funding; DalCor Pharmaceutics: Other: Company SAB member; Pfizer: Other: Speaker, Research Funding; Novo-Nordisc: Research Funding.

scholarly journals FLT3 mutated acute myeloid leukemia: 2021 treatment algorithm

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
Naval Daver ◽  
Sangeetha Venugopal ◽  
Farhad Ravandi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Prognostic Significance ◽  
Treatment Algorithm ◽  
Molecular Testing ◽  
Prognostic Impact ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Acute Myeloid

AbstractApproximately 30% of patients with newly diagnosed acute myeloid leukemia (AML) harbor mutations in the fms-like tyrosine kinase 3 (FLT3) gene. While the adverse prognostic impact of FLT3-ITDmut in AML has been clearly proven, the prognostic significance of FLT3-TKDmut remains speculative. Current guidelines recommend rapid molecular testing for FLT3mut at diagnosis and earlier incorporation of targeted agents to achieve deeper remissions and early consideration for allogeneic stem cell transplant (ASCT). Mounting evidence suggests that FLT3mut can emerge at any timepoint in the disease spectrum emphasizing the need for repetitive mutational testing not only at diagnosis but also at each relapse. The approval of multi-kinase FLT3 inhibitor (FLT3i) midostaurin with induction therapy for newly diagnosed FLT3mut AML, and a more specific, potent FLT3i, gilteritinib as monotherapy for relapsed/refractory (R/R) FLT3mut AML have improved outcomes in patients with FLT3mut AML. Nevertheless, the short duration of remission with single-agent FLT3i’s in R/R FLT3mut AML in the absence of ASCT, limited options in patients refractory to gilteritinib therapy, and diverse primary and secondary mechanisms of resistance to different FLT3i’s remain ongoing challenges that compel the development and rapid implementation of multi-agent combinatorial or sequential therapies for FLT3mut AML.

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