scholarly journals Lung resistance-related protein (LRP) predicts favorable therapeutic outcome in Acute Myeloid Leukemia

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Bibi Kulsoom ◽  
Tahir Sultan Shamsi ◽  
Nasir Ali Afsar
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Outcome ◽  
Related Protein ◽  
Lung Resistance ◽  
Acute Myeloid

scholarly journals Immunovirotherapy with vesicular stomatitis virus and PD-L1 blockade enhances therapeutic outcome in murine acute myeloid leukemia

Blood ◽  
2016 ◽  
Vol 127 (11) ◽  
pp. 1449-1458 ◽  
Author(s):  
Weiwei Shen ◽  
Mrinal M. Patnaik ◽  
Autumn Ruiz ◽  
Stephen J. Russell ◽  
Kah-Whye Peng
Keyword(s):  
Acute Myeloid Leukemia ◽  
Vesicular Stomatitis Virus ◽  
Myeloid Leukemia ◽  
Therapeutic Outcome ◽  
Key Points ◽  
Vesicular Stomatitis ◽  
Immunocompetent Mice ◽  
Acute Myeloid

Key Points IV therapy with oncolytic VSV-IFNβ-NIS virus extends survival of immunocompetent mice with AML. The therapeutic outcome of VSV-IFNβ-NIS–treated mice with AML is augmented by anti-PD-L1 immunotherapy.

scholarly journals Overexpression of the major vault transporter protein lung-resistance protein predicts treatment outcome in acute myeloid leukemia

Blood ◽  
1996 ◽  
Vol 87 (6) ◽  
pp. 2464-2469 ◽  
Author(s):  
AF List ◽  
CS Spier ◽  
TM Grogan ◽  
C Johnson ◽  
DJ Roe ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Prognostic Significance ◽  
Secondary Aml ◽  
Lung Resistance Protein ◽  
Transporter Protein ◽  
Lung Resistance ◽  
Resistance Protein ◽  
Acute Myeloid

The monoclonal antibody LRP56 recognizes a 110-kD major vault protein (lung-resistance protein [LRP]) overexpressed in several P-glycoprotein- negative (Pgp-), multidrug resistant tumor cell lines. To determine the frequency of LRP overexpression, its prognostic significance, and its relation to Pgp, we analyzed bone marrow specimens from 87 consecutive patients with acute leukemia. Diagnoses included de novo acute myeloid leukemia (AML; 21 patients), leukemia arising from an antecedent hematologic disorder or prior cytotoxic therapy (secondary AML; 27 patients), AML in relapse (29 patients), and blast phase of chronic myeloid leukemia (CML-BP; 10 patients). A granular cytoplasmic staining pattern was detected by immunocytochemistry in 32 (37%) cases, including 7 (33%) de novo AML, 13 (48%) secondary AML, 11 (38%) relapsed AML, and 1 of 10 CML-BP. Among 66 evaluable patients with AML, LRP overexpression was associated with an inferior response to induction chemotherapy (P = .0017). Remissions were achieved in 35% of LRP+ patients as compared with 68% of LRP- patients. Although Pgp adversely affected response in univariate analysis (P = .0414), only LRP had independent prognostic significance when compared in a logistic regression model (P = .0046). Differences in remission duration (P = .075) and overall survival (P = .058) approached significance only for LRP. Sequential specimens from remitting patients receiving treatment with the Pgp modulator cyclosporin-A showed emergence of the LRP phenotype despite a decrease or loss of Pgp at the time of treatment failure (P =.0304). Significant associations were observed between LRP and age greater than 55 years (P = .017), Pgp (P = .040), and prior treatment with mitoxantrone (P = .020) but not with CD34. These findings indicate that overexpression of the novel transporter protein LRP is an important predictor of treatment outcome in AML.

Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 18-18
Author(s):  
Matthias Krusch ◽  
Katrin M. Baltz ◽  
Tina Baessler ◽  
Lothar Kanz ◽  
Helmut R. Salih
Keyword(s):  
Acute Myeloid Leukemia ◽  
Nk Cells ◽  
Myeloid Leukemia ◽  
Map Kinases ◽  
Nk Cell ◽  
Immune Surveillance ◽  
Related Protein ◽  
Surface Receptors ◽  
Enhanced Production ◽  
Acute Myeloid

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p<0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p<0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both <0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.

The role of apoptosis, proliferation, and the Bcl-2–related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3932-3938 ◽  
Author(s):  
Jane E. Parker ◽  
Ghulam J. Mufti ◽  
Feyrooz Rasool ◽  
Aleksandar Mijovic ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Disease Progression ◽  
Cell Apoptosis ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Related Protein ◽  
Ki 67 ◽  
Acute Myeloid

Abstract Bone marrow CD34+ cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76.6%]) compared with NBM (16.7% [3.4%-35.3%],P < .0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%];P < .0001) and proliferation (16.8% [1.9%-75.8%);P = .04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P = .06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P < .0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2–related protein expression and apoptosis (P = .07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34+cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2–related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS.

Triggering Noncycling Hematopoietic Progenitors and Leukemic Blasts to Proliferate Increases Anthracycline Retention and Toxicity by Downregulating Multidrug Resistance

Blood ◽  
1999 ◽  
Vol 94 (7) ◽  
pp. 2414-2423 ◽  
Author(s):  
Mariëlle E.P. Smeets ◽  
Reinier A.P. Raymakers ◽  
Gerty Vierwinden ◽  
Arie H.M. Pennings ◽  
Hans Wessels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Multidrug Resistance ◽  
Myeloid Leukemia ◽  
Proliferation Rate ◽  
Related Protein ◽  
Hematopoietic Progenitors ◽  
P Glycoprotein ◽  
Cd34 Cells ◽  
Normal Human ◽  
Acute Myeloid

Expression of the multidrug resistance (MDR) mechanisms P-glycoprotein (Pgp) and MDR-related protein (MRP) decrease cellular retention and consequently cytotoxicity of anthracyclines. MDR is expressed on normal human hematopoietic progenitors and leukemic blasts. Normal CD34+ progenitors showed rhodamine efflux in 20% to 30% of the cells, which could be blocked by verapamil. These cells appeared noncycling, in contrast to the proliferating rhodamine bright (RhoB) cells. We postulated that MDR expression can be downregulated by proliferation induction. Triggering rhodamine dull (RhoD) CD34+ cells to proliferate indeed resulted in a higher rhodamine retention and significantly decreased efflux modulation by verapamil (P = .04). Also in acute myeloid leukemia (AML), the proliferation rate (percentage S/G2+M and Iododeoxyuridine labelings index) was significantly less in the RhoD blasts (P ≤ .008) and proliferation induction of RhoD blasts resulted in increased rhodamine retention. Anthracycline cytotoxicity was less for RhoD than RhoB cells in both normal progenitors and leukemic blasts. Proliferation induction of the RhoD cells resulted in increased anthracycline sensitivity. We conclude that noncycling progenitors, both normal and leukemic, have a relatively high MDR expression. Triggering these cells into proliferation downregulates MDR expression. These findings can be exploited to overcome MDR in the treatment of AML patients.

scholarly journals Glucocorticoid-Induced Tumor Necrosis Factor Receptor–Related Protein Ligand Subverts Immunosurveillance of Acute Myeloid Leukemia in Humans

2009 ◽  
Vol 69 (3) ◽  
pp. 1037-1045 ◽  
Author(s):  
Tina Baessler ◽  
Matthias Krusch ◽  
Benjamin Joachim Schmiedel ◽  
Mercedes Kloss ◽  
Katrin Miriam Baltz ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Tumor Necrosis Factor ◽  
Myeloid Leukemia ◽  
Tumor Necrosis ◽  
Tumor Necrosis Factor Receptor ◽  
Related Protein ◽  
Necrosis Factor ◽  
Acute Myeloid

The role of apoptosis, proliferation, and the Bcl-2–related proteins in the myelodysplastic syndromes and acute myeloid leukemia secondary to MDS

Blood ◽  
2000 ◽  
Vol 96 (12) ◽  
pp. 3932-3938 ◽  
Author(s):  
Jane E. Parker ◽  
Ghulam J. Mufti ◽  
Feyrooz Rasool ◽  
Aleksandar Mijovic ◽  
Stephen Devereux ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Protein Expression ◽  
Disease Progression ◽  
Cell Apoptosis ◽  
Myeloid Leukemia ◽  
Refractory Anemia ◽  
International Prognostic Scoring System ◽  
Related Protein ◽  
Ki 67 ◽  
Acute Myeloid

Bone marrow CD34+ cell apoptosis (annexin V), proliferation (Ki-67), and Bcl-2-related protein expression was evaluated by flow cytometry in 102 patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia secondary to MDS (MDS-AML) and in 30 normal donors (NBM). Apoptosis was significantly increased in refractory anemia (RA)/RA with ringed sideroblasts (RARS) (56.9% [20.4%-93.6%]) and refractory anemia with excess blasts (RAEB) (51.2% [25.2%-76.6%]) compared with NBM (16.7% [3.4%-35.3%],P < .0001). In RA/RARS, apoptosis always exceeded proliferation (Ki-67-positivity, 26.1% [9.5%-47.8%]; apoptosis:proliferation ratio 2.08 [1.15-3.63]); whereas in RAEB, this ratio equalized (1.14 [0.93-2.08]) due to increased proliferation (40.4% [22%-69.5%]). Progression to RAEB in transformation (RAEB-t)/MDS-AML was associated with a significant reduction in apoptosis (22.3% [2.1%-53.2%];P < .0001) and proliferation (16.8% [1.9%-75.8%);P = .04; ratio 1.69 [0.16-12.21]). Pro-apoptotic (Bax/Bad) versus anti-apoptotic (Bcl-2/Bcl-X) Bcl-2-related protein ratios were increased in RA/RARS compared with NBM (2.57 [1.93-9.42] versus 1.89 [0.65-4.1]; P = .06), whereas disease progression was associated with significantly reduced ratios (1.16 [0.06-3.32]; P < .0001) due primarily to increased Bcl-2 expression. Apoptosis and Bax/Bad:Bcl-2/Bcl-X ratio were inversely correlated with both International Prognostic Scoring System score and cytogenetic risk group; highest levels observed in patients with low score and/or good risk cytogenetics. There was a trend toward an association between Bcl-2–related protein expression and apoptosis (P = .07). This study indicates that MDS progression arises through multiple hits that alter levels of CD34+cell apoptosis and proliferation. Early disease is associated with excessive apoptosis and elevated ratio of apoptosis to proliferation. Increased proliferative rates are observed in RAEB, whereas leukemic transformation arises through inhibition of apoptosis rather than excessive cell growth. Although disease progression is accompanied by a fall in pro-apoptotic versus anti-apoptotic Bcl-2–related protein ratios, heterogeneity in patterns of protein expression indicates that factors additional to Bcl-2 family members play a role in the deregulated apoptosis in MDS.

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