CXCR4 as a Predictor of Response in Acute Myeloid Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2941-2941
Author(s):  
Domenico Pastore ◽  
Anna Mestice ◽  
Margherita Giannoccaro ◽  
Arcangelo Liso ◽  
Maria Paola Martelli ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Negative Regulator ◽  
Leukemic Cells ◽  
Common Mutation ◽  
Response To Chemotherapy ◽  
Significant Difference ◽  
Induced Apoptosis ◽  
Acute Myeloid

Abstract The expression of CXCR4 (CD184) has been associated with poor prognosis in Acute Myeloid Leukemia (AML) and it has also been suggested that the CXCL12(SDF-1a)/CXCR4 interaction contributes to the resistance of leukemia cells to chemotherapy-induced apoptosis. Inhibition of CXCR4 was found to enhance chemotherapy-induced apoptosis in a subset of leukemic myeloblasts that carry Flt3 mutations and to overcome chemoresistance associated with stromal activity. NPM variants with a cytoplasmic localization represent the most common mutation detected in myeloid malignancies and are associated with a favourable clinical outcome. A recent study provides biological evidence for a novel role for NPM as a negative regulator of CXCR4 signalling induced by CXCL12: suppression of NPM expression enhanced chemotactic responses to CXCL12, and conversely, over-expression of a cytosolic NPM mutant reduced chemotaxis induced by CXCL12. We investigated whether CD184 expression is a negative predictor factor for response to chemotherapy and if there is clinical evidence that NPM mutations could overcome chemoresistance to induction therapy in this subset of patients. The expression of CD184 was analyzed by flow cytometric methods in a group of 70 cases of adult AML at onset of disease, diagnosed at our Institution since January 2006. The diagnosis was performed according to FAB/WHO criteria; all patients received intensive chemotherapy according to institutional protocols. There were 34 males and 36 females and median age was 46 years (range 18–65). AML cells were gated based upon their CD45 expression and samples were considered positive if CD184 was expressed by more than 20% of blasts. CD184 was positive in 45 and negative in 25 cases. There was no significant difference between the two groups in terms of sex, age, Hb level, WBC and Plt counts, percentage of blasts, and occurrence of the NPM mutation. The CR rate was 45% in CD184+ and 82% in CD184- (p=0.03); among CD184+ cases, the CR rate was significantly higher in NPMc+ cases, (p=0.03). Our results show that CD184 expression is associated with a lower rate of CR after induction therapy and this association is stronger in NPM unmutated cases, suggesting that CD184 expression is a negative predictive factor for response to chemotherapy. Further data are needed to verify if the biological role of the cytosolic NPM mutant as a negative regulator of CXCR4 signalling induced by CXCL12 could have a clinical role contributing to overcome the resistance of leukemic cells to induction chemotherapy.

scholarly journals The Expression Changes of CX3CL1 and Interlukin-6 Genes During Remission Induction Therapy in Patients With Acute Myeloid Leukemia

2021 ◽  
Vol 10 ◽  
pp. e2288
Author(s):  
Mahdiyar Iravani Saadi ◽  
Mani Ramzi ◽  
Aliasghar Karimi ◽  
Maryam Owjfard ◽  
Mahmoud Torkamani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Hematologic Malignancy ◽  
Quantitative Polymerase Chain Reaction ◽  
Remission Induction ◽  
Response To Chemotherapy ◽  
Before And After ◽  
Acute Myeloid

Background: Acute Myeloid Leukemia syndrome (AML) is a hematologic malignancy which is due to clonal extensive proliferation of leukemic precursor cells and is rapidly fatal unless treated or response to chemotherapy. Cytogenetic findings have important role in prognosis and categorization of AML. The aim of this study was to investigate the expression changes in CX3CL1 and Interlukin-6 (IL-6) genes before and after chemotherapy as remission induction therapy in AML patients. Materials and Methods: In this study 69 patients (36 males, 33 female) with AML was selected from tertiary medical heath center. A quantitative polymerase chain reaction (PCR) was done for mRNA expression of CX3CL1 and IL-6genes before and after induction chemotherapy. To obtain expression changes in CX3CL1 and IL-6genes, we used 2-ΔΔCT method. Results: The expression of CX3CL1 and IL-6 was significantly increased after induction chemotherapy. Also, the ΔCt mean of CX3CL1 and IL-6 mRNA was not significant between AML subtype groups. Conclusion: In conclusion, as we showed that chemotherapy significantly increase the expression of CX3CL1 and IL-6 which can be used as a prognostic factor of AML.

scholarly journals High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3091-3096 ◽  
Author(s):  
L Campos ◽  
JP Rouault ◽  
O Sabido ◽  
P Oriol ◽  
N Roubi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Protein ◽  
High Expression ◽  
Leukemic Cells ◽  
Stem Cell Marker ◽  
Cell Counts ◽  
Response To Chemotherapy ◽  
Acute Myeloid

The BCL-2 proto-oncogene encodes a mitochondrial protein that blocks programmed cell death. High amounts of bcl-2 protein are found not only in lymphoid malignancies, but also in normal tissues characterized by apoptotic cell death, including bone marrow. Using a monoclonal antibody to bcl-2 protein, we analyzed 82 samples of newly diagnosed acute myeloid leukemia. The number of bcl-2+ cells in each sample was heterogeneous (range, 0% to 95%), with a mean of 23%. The percentage of bcl-2+ cells was higher in M4 and M5 types, according to French- American-British classification, and in cases with high white blood cell counts. bcl-2 expression was also correlated with that of the stem cell marker CD34. In vitro survival of leukemic cells maintained in liquid culture in the absence of growth factors was significantly longer in cases with a high percentage of bcl-2+ cells. High expression of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (29% in cases with 20% or more positive cells v 85% in cases with less than 20% positive cells, P < 10(-5)) and with a significantly shorter survival. In multivariate analysis, the percentage of bcl-2+ cells (or the blast survival in culture), age, and the percentage of CD34+ cells were independently associated with poor survival.

scholarly journals High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy

Blood ◽  
1993 ◽  
Vol 81 (11) ◽  
pp. 3091-3096 ◽  
Author(s):  
L Campos ◽  
JP Rouault ◽  
O Sabido ◽  
P Oriol ◽  
N Roubi ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Mitochondrial Protein ◽  
High Expression ◽  
Leukemic Cells ◽  
Stem Cell Marker ◽  
Cell Counts ◽  
Response To Chemotherapy ◽  
Acute Myeloid

Abstract The BCL-2 proto-oncogene encodes a mitochondrial protein that blocks programmed cell death. High amounts of bcl-2 protein are found not only in lymphoid malignancies, but also in normal tissues characterized by apoptotic cell death, including bone marrow. Using a monoclonal antibody to bcl-2 protein, we analyzed 82 samples of newly diagnosed acute myeloid leukemia. The number of bcl-2+ cells in each sample was heterogeneous (range, 0% to 95%), with a mean of 23%. The percentage of bcl-2+ cells was higher in M4 and M5 types, according to French- American-British classification, and in cases with high white blood cell counts. bcl-2 expression was also correlated with that of the stem cell marker CD34. In vitro survival of leukemic cells maintained in liquid culture in the absence of growth factors was significantly longer in cases with a high percentage of bcl-2+ cells. High expression of bcl-2 was associated with a low complete remission rate after intensive chemotherapy (29% in cases with 20% or more positive cells v 85% in cases with less than 20% positive cells, P < 10(-5)) and with a significantly shorter survival. In multivariate analysis, the percentage of bcl-2+ cells (or the blast survival in culture), age, and the percentage of CD34+ cells were independently associated with poor survival.

scholarly journals The pan-Bcl-2 inhibitor obatoclax promotes differentiation and apoptosis of acute myeloid leukemia cells

2020 ◽  
Vol 38 (6) ◽  
pp. 1664-1676
Author(s):  
Małgorzata Opydo-Chanek ◽  
Iwona Cichoń ◽  
Agnieszka Rak ◽  
Elżbieta Kołaczkowska ◽  
Lidia Mazur
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Strategies ◽  
Leukemic Cell ◽  
Leukemic Cells ◽  
Dependent Manner ◽  
Apoptotic Pathway ◽  
Acute Myeloid Leukemia Cells ◽  
Induced Apoptosis ◽  
Acute Myeloid

Summary One of the key features of acute myeloid leukemia (AML) is the arrest of differentiation at the early progenitor stage of myelopoiesis. Therefore, the identification of new agents that could overcome this differentiation block and force leukemic cells to enter the apoptotic pathway is essential for the development of new treatment strategies in AML. Regarding this, herein we report the pro-differentiation activity of the pan-Bcl-2 inhibitor, obatoclax. Obatoclax promoted differentiation of human AML HL-60 cells and triggered their apoptosis in a dose- and time-dependent manner. Importantly, obatoclax-induced apoptosis was associated with leukemic cell differentiation. Moreover, decreased expression of Bcl-2 protein was observed in obatoclax-treated HL-60 cells. Furthermore, differentiation of these cells was accompanied by the loss of their proliferative capacity, as shown by G0/G1 cell cycle arrest. Taken together, these findings indicate that the anti-AML effects of obatoclax involve not only the induction of apoptosis but also differentiation of leukemic cells. Therefore, obatoclax represents a promising treatment for AML that warrants further exploration.

scholarly journals ERK Activity in Immature Leukemic Cells Drives Clonal Selection during Induction Therapy for Acute Myeloid Leukemia

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Michal Hayun ◽  
Maria Zaatra ◽  
Chen Itzkovich ◽  
Dvora Sahar ◽  
Dina Rosenberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Clonal Selection ◽  
Leukemic Cells ◽  
Erk Activity ◽  
Acute Myeloid

Variations in Proteasome Enzymatic Activities in Plasma of Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome and Their Value in Predicting Clinical Behavior.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4497-4497 ◽  
Author(s):  
Wanlong Ma ◽  
Francis Giles ◽  
Susan O’Brien ◽  
Iman Jilani ◽  
Xi Zhang ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Performance Status ◽  
Proteasome Inhibitors ◽  
Leukemic Cells ◽  
Clinical Behavior ◽  
Cytogenetic Abnormalities ◽  
Significant Difference ◽  
And Performance ◽  
Acute Myeloid

Abstract The ubiquitin-proteasome pathway is responsible for multiple pathways in cancer cells; proteasome inhibition causes rapid apoptosis of tumor cells. Three different types of peptidase activities have been reported for proteasomes: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L) (postglutamyl peptide hydrolytic-like). Various proteasome inhibitors affect each of the 3 activities differently and at different concentrations. For example, NPI-0052 inhibits Ch-L and Tr-L activities at lower concentrations than does bortezomib, while bortezomib inhibits Cas-L at lower concentrations than does NPI-0052. These enzymatic activities are usually measured in normal or tumor cells to monitor therapy with proteasome inhibitors. Because rapidly proliferating leukemic cells pour their proteins, DNA, and RNA into the circulation, we developed fluorogenic kinetic assays using peripheral blood plasma. The assays used peptide-AMC (7-amino 4-methylcoumoran) substrates to measure Ch-L, Tr-L, and Cas-L activities. We measured proteasome activities in plasma from 188 patients with acute myeloid leukemia (AML) and 58 patients with myelodysplastic syndrome (MDS) and assessed their correlations with clinical behavior. Significantly (P &lt; 0.001) higher Ch-L, Tr-L, and Cas-L activities were seen in AML patients (medians: 1.39, 1.51, and 2.40 pmol AMC/sec/mL, respectively) and MDS patients (medians: 1.16, 1.40, and 1.67 pmol AMC/sec/mL, respectively) than in healthy volunteers (n=42) (medians: 0.80, 0.74, and 0.81 pmol AMC/sec/mL, respectively). The difference in Cas-L activity between AML and MDS was significant (P &lt;0.001). While there was no significant difference between Ch-L and Cas-L activities in healthy controls, there was a significant difference between the 2 activities in both AML and MDS. Cas-L and Ch-L, but not Tr-L, correlated with WBC count and lactic dehydrogenase in AML and MDS patients. In AML patients, higher levels of Ch-L and Cas-L were associated with poor response to a variety of therapies (P = 0.004 and P = 0.001, respectively). Cas-L correlated strongly with survival in AML patients when used as an activity-dependent variable (P &lt;0.001) or when the median was used as a cut-off (P = 0.004). This was independent of cytogenetic abnormalities, age, and performance status. Patients with intermediate-risk cytogenetic abnormalities and Cas-L activity &gt;3 pmol AMC/sec/mL had significantly shorter survival (P = 0.04). Ch-L activity was also predictive of survival in AML independent of age and cytogenetic and performance status, but not independent of Cas-L. In MDS, higher levels of Cas-L, but not Ch-L, correlated with shorter survival and this was independent of cytogenetic abnormalities. The increased cell-free circulating proteasome activities most likely reflect the leukemic cells and may be a marker not only for disease, but also potentially for monitoring therapy. These data also suggest that patients with AML may benefit differentially from proteasome inhibitors depending on the specific therapeutic effect of the inhibitor.

scholarly journals Compared the Effect of Mitroxantrone ( MA) with Idarubicine (IA) for Acute Myeloid Leukemia Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5229-5229
Author(s):  
Peilong Lai ◽  
Mingyan Wu ◽  
Minming Li ◽  
Chengxin Deng ◽  
Zesheng Lu ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Complete Response ◽  
Platelet Recovery ◽  
Significant Difference ◽  
Induction Regimen ◽  
Event Rates ◽  
Acute Myeloid

Abstract Background: Treatment for acute myeloid leukemia (AML) has remained relatively unchanged over the past few decades. Standard-dose cytarabine and idarubicin (7+3 IA) or daunorubicin (7+3 DA) induction regimen have been recommended for AML induction therapy by global guidelines. Mitroxantrone, a type II topoisomerase inhibitor, disrupts DNA synthesis and DNA repair, has been recommended as a salvage treatment for refractory/relapsed AML or induction therapy for elderly patients. Objective: To compare the the clinical response and adverse events of Idarubicin regimen ( IA) with mitoxantrone and cytarabine (MA) in the treatment of newly acute myeloid leukemia (AML) . Methods: This retrospective study evaluated 164 patients with newly diagnosed AML who received either IA (idarubicin 10mg/M2, d1-3; cytarabine 200mg/d, d1-7) or MA regimen (mitoxantrone 10mg/M2, d1-d3; cytarabine 200mg/d, d1-7) as induction therapy from September 2010 to November 2017 at Guangdong General Hospital. The primary end point of this study was complete response and complete response with incomplete blood count recovery (CR/CRi), with secondary end points were adverse event rates and days of granulocyte and platelet recovery. Results: A total of 164 patients , 90 patients were males and 74 females, the median age was 41 (range:14~64) years old. There were 88 patients received IA regimen and 76 patients received MA regimen. There was no significant difference in clinical features and molecular biological characteristics in two groups (P>0.05). The CR/CRi rate was 72.3% and 64.0% (P=0.263) in IA and MA group after the first induction regimen, respectively. And the accumulated CR/CRi rate was 85.9% and 75.7% in two group, respectively (P=0.109). The common adverse reactions in the two groups were myelosuppression and infection , but with no statistical difference (P>0.05) in the incidence and grade of serious. The grade 4 and grade 5 neutropenia were 95.3% vs.98.7% and 4.7% vs. 1.3%, P>0.05 in IA and MA group respectively. And thrombocytpenia were 72.9% vs.63.2% and 4.7% vs. 1.3%, P>0.05. There was no significant difference in the incidence and severity of gastrointestinal, cardiovascular, respiratory, skin, liver and kidney injury between the two groups (P>0.05). The median days of intravenous antibiotics (including antifungal drugs), neutrophil recovery, platelet recovery and the units of platelet and red blood cell suspension transfusion had no statistical difference in two groups (P>0.05). Conclusion: This retrospective study implied mitoxantrone with standard-dose cytarabine (3+7 MA) regimen has similar efficacy and outcome to the idarubicin with standard-dose cytarabine (3+7 IA) regimen for newly diagnosed AML, without increasing the incidence of adverse event rates. Disclosures No relevant conflicts of interest to declare.

P-Glycoprotein Inhibitor Valspodar (PSC 833) Increases the Intracellular Concentrations of Daunorubicin In Vivo in Patients With P-Glycoprotein–Positive Acute Myeloid Leukemia

2000 ◽  
Vol 18 (9) ◽  
pp. 1837-1844 ◽  
Author(s):  
U. Tidefelt ◽  
J. Liliemark ◽  
A. Gruber ◽  
E. Liliemark ◽  
B. Sundman-Engberg ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Area Under The Curve ◽  
Leukemic Cells ◽  
Psc 833 ◽  
P Glycoprotein ◽  
Significant Difference ◽  
The Mean ◽  
Acute Myeloid

PURPOSE: The aim of the present study was to evaluate the effect of the cyclosporine derivative valspodar (PSC 833; Amdray, Novartis Pharma, Basel, Switzerland) on the concentration of daunorubicin (dnr) in leukemic blast cells in vivo during treatment.PATIENTS AND METHODS: Ten patients with acute myeloid leukemia (AML) were included. Leukemic cells from seven of the patients were P-glycoprotein (Pgp)–positive. dnr 100 mg/m2was given as a continuous infusion over 72 hours. After 24 hours, a loading dose of valspodar was given, followed by a 36-hour infusion of 10 mg/kg per 24 hours. Blood samples were drawn at regular intervals, and concentrations of dnr and its main metabolite, daunorubicinol, in plasma and isolated leukemic cells were determined by high-pressure liquid chromatography.RESULTS: The mean dnr concentrations in leukemic cells 24 hours after the start of infusion (before valspodar) were 18.8 μmol/L in Pgp-negative samples and 13.5 μmol/L in Pgp-positive samples. After 8 hours of valspodar infusion, these values were 25.8 and 24.0 μmol/L, respectively. The effect of valspodar was evaluated from the ratio of the area under the curve (AUC) for dnr concentration versus time in leukemic cells to the AUC for dnr concentration against time in the plasma. For the seven patients with Pgp-positive leukemia, the mean ratio increased by 52%, from 545 on day 1 to 830 on day 2 (P < .05) when valspodar was given. In the three patients with Pgp-negative leukemia, no significant difference was observed.CONCLUSION: These results strongly suggest that valspodar, by interacting with Pgp, can increase the cellular uptake of dnr in leukemic blasts in vivo.

scholarly journals Genetic variants of nucleotide excision repair pathway and outcomes of induction therapy in acute myeloid leukemia

2019 ◽  
Vol 16 (6) ◽  
pp. 479-490
Author(s):  
Zohreh Sharifi ◽  
Mohammad Faranoush ◽  
Alireza Mohseni ◽  
Shahrbano Rostami ◽  
Mani Ramzi ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nucleotide Excision Repair ◽  
Induction Therapy ◽  
Genetic Variants ◽  
Myeloid Leukemia ◽  
Excision Repair ◽  
Response To Therapy ◽  
Response To Chemotherapy ◽  
Nucleotide Excision ◽  
Acute Myeloid

Aim: Acute myeloid leukemia (AML) is a heterogeneous disease in pathogenesis and response to therapy. Nucleotide excision repair (NER) pathway has a major role in the elimination of genotoxic effects of chemotherapeutic agents. We aimed to clarify the effects of selected variants of XPD, XPC, ERCC5 and ERCC1 genes on the outcomes of induction therapy. Materials & methods: The prevalence of NER genetic variants was evaluated in 67 subjects with AML and their effects on clinical outcomes were analyzed by χ2 test. Results: The XPD 751 Lys variant was associated with improved response to chemotherapy compared with XPD 751 Gln and Lys/Gln variants (p = 0.023; odds ratio: 4.5; 95% CI: 1.14–17.73). There were no associations between other genotypes and any outcomes. Conclusion: Current findings suggest that XPD Lys751Gln variant could be considered as a prognostic factor in AML.

scholarly journals Reduced Expression of Sprouty1 Contributes to the Aberrant Proliferation and Impaired Apoptosis of Acute Myeloid Leukemia Cells

2019 ◽  
Author(s):  
Valentina Rosso ◽  
Crisitina Panuzzo ◽  
Jessica Petiti ◽  
Sonia Carturan ◽  
Matteo Dragani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tyrosine Kinases ◽  
Myeloid Leukemia ◽  
Ectopic Expression ◽  
Negative Regulator ◽  
Leukemic Cells ◽  
Leukemia Cells ◽  
Ras Signaling ◽  
Acute Myeloid Leukemia Cells ◽  
Acute Myeloid

In most of acute myeloid leukemia patients there is an aberrant tyrosine kinases activity. The Sprouty family proteins were originally identified in Drosophila melanogaster as antagonists of Breathless, the mammalian ortholog of fibroblast growth factor receptor. This family proteins are inhibitors of RAS signaling induced by tyrosine kinases receptors and they are implicated in negative feedback processes regulating several intracellular pathways. The present study aims to investigate the role of a member of the Sprouty family, Sprouty1, as regulator of cell proliferation and growth in patients affected by acute myeloid leukemia. Sprouty1 mRNA and protein were both significantly down-regulated in acute myeloid leukemia cells compared to the normal counterpart, but they were restored when remission is achieved after chemotherapy. Ectopic expression of Sprouty1 revealed that it plays a key role in the proliferation and apoptotic defect that represent a landmark of the leukemic cells. Our study identified Sprouty1 as negative regulator involved in the aberrant signals of acute myeloid leukemia. Furthermore, we found a correlation between Sprouty1 and FoxO3a delocalization in AML at diagnosis, suggesting a multistep regulation of RAF&ndash;MEK&ndash;ERK signaling in human cancers.&nbsp;

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