scholarly journals CD34 is a target for covalent EGFR inhibitors to eliminate stem/progenitor cells in acute and chronic myeloid leukemia

2021 ◽  
Author(s):  
Ying Lu ◽  
Li Xia ◽  
Li-Xue Yang ◽  
Hong-Chen Liu ◽  
Yue Jiang ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Growth Factor Receptor ◽  
Egfr Inhibitors ◽  
Stem Cell Marker ◽  
Cd34 Antigen ◽  
Egfr Expression ◽  
Stat3 Phosphorylation

Abstract The effect of epidermal growth factor receptor (EGFR) inhibitors on acute myeloid leukemia (AML) was discovered over one decade ago. However, clinical trials of EGFR inhibitors in AML have yielded controversial outcomes. Leukemia cells lack EGFR expression, and the mechanism by which EGFR inhibitors affect leukemia cell growth is unknown, obscuring the precise subset of AML patients that might be targeted by these compounds. Since myeloid leukemia arises from malignant stem/progenitors, here we evaluated the effect of EGFR inhibitors on primary leukemia stem/progenitors that expressed the stem cell marker CD34 which were sorted from leukemia patients. EGFR inhibitors induced significant apoptosis of primary CD34+ but not CD34− cells derived from AML and chronic myeloid leukemia (CML) patients both in vitro and in patient-derived xenotransplantation model. Using two EGFR inhibitors osimertinib and afatinib, we demonstrated binding and covalent adducts of the inhibitors with the cysteine(C) 199 residue of the CD34 protein, which downregulated phosphorylation of tyrosine 329(Y329) of CD34, leading to the dissociation of CD34 from tyrosine kinase Src and thereafter the inhibition of STAT3 phosphorylation. Most importantly, administration of osimertinib yielded clinical responses in two CD34-high AML patients identified by quantitative proteomics with reduced levels of Y329 phosphorylation of CD34 after treatment. Collectively, these findings delineate a novel molecular pathway whereby EGFR inhibitors kill leukemia and reveal that the CD34 antigen is a targetable signaling molecule that mediates cell survival signals via connecting to Src-STAT3 pathway.

Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2198-2203 ◽  
Author(s):  
Liquan Gao ◽  
Ilaria Bellantuono ◽  
Annika Elsässer ◽  
Stephen B. Marley ◽  
Myrtle Y. Gordon ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Progenitor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Leukemia Cell

Abstract Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.

Characterization of Bcr-Abl Positive Leukemic Cells under Long-Term In Vitro Treatment with Telomerase Inhibitor BIBR1532.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2185-2185
Author(s):  
Ute Brassat ◽  
Stefan Balabanov ◽  
Ulrike Hartmann ◽  
Daniel Rössler ◽  
Kerstin Borgmann ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Chromosome 9 ◽  
Leukemia Cell Line ◽  
Telomere Shortening ◽  
Telomerase Inhibition ◽  
Telomerase Inhibitor

Abstract In normal somatic cells telomeres shorten with each cell division because of the end-replication problem. The ribonucleoprotein enzyme telomerase is able to prevent replicative telomere shortening and to maintain or elongate telomere length. In 90 % of tumour cells the enzyme telomerase is found to be upregulated. Chronic myeloid leukemia is a disorder characterized by a reciprocal translocation between Chromosome 9 and 22, leading to the so called Philadelphia chromosome harbouring the BCR-ABL translocation. BCR-ABL positive leukemic stem cells are characterized by increased turnover leading to accelerated telomere shortening as opposed to their normal counterparts. It is unclear to date whether accelerated telomere shortening in Bcr-Abl-positive cells is linked to genetic instability eventually leading to the acquisition of secondary clonal events that might propagate acceleration of the disease to blast crisis. Therefore we aimed to characterize Bcr-Abl positive chronic myeloid leukemia cell line K562 with or without inhibition of telomerase activity under long-term culture conditions. K652 cells were expanded for 400 populations doublings (PD) with or without treatment with the small molecule telomerase inhibitor BIBR1532 in vitro. While telomeres in untreated control cells remained relatively constant, telomeres in BIBR1532 treated cells underwent replicative shortening from 10 kb to 3 kb (as measured by flow FISH), reflecting a rate of 22 base pairs (bp) lost per PD. No difference in growth kinetics were observed until that stage. We next characterized treated K562 with short telomeres (K562-S) in contrast to control cells with long telomeres (K562-L) for the expression of telomere and telomerase-binding proteins. No difference in mRNA expression for any of the candidate proteins were observed by RT-PCR. Comparative analysis of global protein expression was performed by 2D gel electrophoresis. Taken together, 23 protein spots were found to be differentially expressed between treated and untreated cells, fifteen of which were already identified by mass spectometry. Additionally, we analysed the cells for the acquisition of additional cytogenetic abnormalities by M-FISH. Interestingly, in this ongoing study, we consistently found acquisition of genetic material on chromosome 7 in treated as compared to untreated cells. To study radiation sensitivity under BIBR1532 treatment, K562 cells were exposed to increasing doses of irradiation. Interestingly, despite of a dose-dependent increase in the fraction of apoptotic cells in the pre-treated as opposed to control cells, no accumulation in the number of double strand breaks or lethal aberrations were detected. Interestingly, telomere shortening after telomerase inhibition translated to increased sensitivity to Imatinib (IC50 0.6 μM vs. IC50 1.2 μM). Taken together, telomerase inhibition represent a attractive new therapeutic strategy in Bcr-Abl positive leukemias. However, careful evaluation of side effects need to be studied on the proteomics and cytogenetic level.

Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1

Blood ◽  
2000 ◽  
Vol 95 (7) ◽  
pp. 2198-2203 ◽  
Author(s):  
Liquan Gao ◽  
Ilaria Bellantuono ◽  
Annika Elsässer ◽  
Stephen B. Marley ◽  
Myrtle Y. Gordon ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Chronic Myeloid Leukemia ◽  
T Lymphocytes ◽  
Progenitor Cells ◽  
Cytotoxic T Lymphocytes ◽  
Colony Formation ◽  
Myeloid Leukemia ◽  
Leukemia Cell

Hematologic malignancies such as acute and chronic myeloid leukemia are characterized by the malignant transformation of immature CD34+ progenitor cells. Transformation is associated with elevated expression of the Wilm's tumor gene encoded transcription factor (WT1). Here we demonstrate that WT1 can serve as a target for cytotoxic T lymphocytes (CTL) with exquisite specificity for leukemic progenitor cells. HLA-A0201– restricted CTL specific for WT1 kill leukemia cell lines and inhibit colony formation by transformed CD34+ progenitor cells isolated from patients with chronic myeloid leukemia (CML), whereas colony formation by normal CD34+ progenitor cells is unaffected. Thus, the tissue-specific transcription factor WT1 is an ideal target for CTL-mediated purging of leukemic progenitor cells in vitro and for antigen-specific therapy of leukemia and other WT1-expressing malignancies in vivo.

scholarly journals LRIG1 is a conserved EGFR regulator involved in melanoma development, survival and treatment resistance

Oncogene ◽  
2021 ◽  
Author(s):  
Ola Billing ◽  
Ylva Holmgren ◽  
Daniel Nosek ◽  
Håkan Hedman ◽  
Oskar Hemmingsson
Keyword(s):  
Growth Factor Receptor ◽  
Braf Inhibitor ◽  
Treatment Resistance ◽  
Negative Regulator ◽  
C Elegans ◽  
Rtk Signaling ◽  
Egfr Expression ◽  
Inhibitor Resistance ◽  
Leucine Rich Repeats

AbstractLeucine-rich repeats and immunoglobulin-like domains 1 (LRIG1) is a pan-negative regulator of receptor tyrosine kinase (RTK) signaling and a tumor suppressor in several cancers, but its involvement in melanoma is largely unexplored. Here, we aim to determine the role of LRIG1 in melanoma tumorigenesis, RTK signaling, and BRAF inhibitor resistance. We find that LRIG1 is downregulated during early tumorigenesis and that LRIG1 affects activation of the epidermal growth factor receptor (EGFR) in melanoma cells. LRIG1-dependent regulation of EGFR signaling is evolutionary conserved to the roundworm C. elegans, where negative regulation of the EGFR-Ras-Raf pathway by sma-10/LRIG completely depends on presence of the receptor let-23/EGFR. In a cohort of metastatic melanoma patients, we observe an association between LRIG1 and survival in the triple wild-type subtype and in tumors with high EGFR expression. During in vitro development of BRAF inhibitor resistance, LRIG1 expression decreases; and mimics LRIG1 knockout cells for increased EGFR expression. Treating resistant cells with recombinant LRIG1 suppresses AKT activation and proliferation. Together, our results show that sma-10/LRIG is a conserved regulator of RTK signaling, add to our understanding of LRIG1 in melanoma and identifies recombinant LRIG1 as a potential therapeutic against BRAF inhibitor-resistant melanoma.

scholarly journals Hyaluronan oligomers sensitize chronic myeloid leukemia cell lines to the effect of Imatinib

Glycobiology ◽  
2015 ◽  
Vol 26 (4) ◽  
pp. 343-352 ◽  
Author(s):  
Silvina Laura Lompardía ◽  
Mariángeles Díaz ◽  
Daniela Laura Papademetrio ◽  
Marilina Mascaró ◽  
Matías Pibuel ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Cell Lines ◽  
Myeloid Leukemia ◽  
Leukemia Cell ◽  
Chronic Myeloid Leukemia Cell ◽  
Leukemia Cell Lines ◽  
Myeloid Leukemia Cell

scholarly journals (Phenylamino)pyrimidine-1,2,3-triazole derivatives as analogs of imatinib: searching for novel compounds against chronic myeloid leukemia

2021 ◽  
Vol 17 ◽  
pp. 2260-2269
Author(s):  
Luiz Claudio Ferreira Pimentel ◽  
Lucas Villas Boas Hoelz ◽  
Henayle Fernandes Canzian ◽  
Frederico Silva Castelo Branco ◽  
Andressa Paula de Oliveira ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Competitive Inhibition ◽  
Leukemia Cell ◽  
Docking Studies ◽  
Leukemia Cell Line ◽  
Inhibition Mechanism ◽  
Triazole Derivatives

The enzyme tyrosine kinase BCR-Abl-1 is the main molecular target in the treatment of chronic myeloid leukemia and can be competitively inhibited by tyrosine kinase inhibitors such as imatinib. New potential competitive inhibitors were synthesized using the (phenylamino)pyrimidine-pyridine (PAPP) group as a pharmacophoric fragment, and these compounds were biologically evaluated. The synthesis of twelve new compounds was performed in three steps and assisted by microwave irradiation in a 1,3-dipolar cycloaddition to obtain 1,2,3-triazole derivatives substituted on carbon C-4 of the triazole nucleus. All compounds were evaluated for their inhibitory activities against a chronic myeloid leukemia cell line (K562) that expresses the enzyme tyrosine kinase BCR-Abl-1 and against healthy cells (WSS-1) to observe their selectivity. Three compounds showed promising results, with IC50 values between 1.0 and 7.3 μM, and were subjected to molecular docking studies. The results suggest that such compounds can interact at the same binding site as imatinib, probably sharing a competitive inhibition mechanism. One compound showed the greatest interaction affinity for BCR-Abl-1 in the docking studies.

scholarly journals Anti-leukemia properties of cadmium nanoparticles in the in vitro and in vivo condition: A chemobiological study

2021 ◽  
Author(s):  
Yudi Miao ◽  
Behnam Mahdavi ◽  
Mohammad Zangeneh
Keyword(s):  
Acute Myeloid Leukemia ◽  
Cell Lines ◽  
Aqueous Extract ◽  
Myeloid Leukemia ◽  
Antioxidant Properties ◽  
Leukemia Cell ◽  
Sem Images ◽  
Acute Myeloid

IntroductionThe present study investigated the anti-acute myeloid leukemia effects of Ziziphora clinopodides Lam leaf aqueous extract conjugated cadmium nanoparticles.Material and methodsTo synthesize CdNPs, Z. clinopodides aqueous extract was mixed with Cd(NO3)2 .4H2O. The characterization of the biosynthesized cadmium nanoparticles was carried out using many various techniques such as UV-Vis. and FT-IR spectroscopy, XRD, FE-SEM, and EDS.ResultsThe uniform spherical morphology of NPs was proved by FE-SEM images with NPs the average size of 26.78cnm. For investigating the antioxidant properties of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, the DPPH test was used. The cadmium nanoparticles inhibited half of the DPPH molecules in a concentration of 196 µg/mL. To survey the cytotoxicity and anti-acute myeloid leukemia effects of Cd(NO3)2, Z. clinopodides, CdNPs, and Daunorubicin, MTT assay was used on the human acute myeloid leukemia cell lines i.e., Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr. The IC50 of the cadmium nanoparticles was 168, 205, and 210 µg/mL against Murine C1498, 32D-FLT3-ITD, and Human HL-60/vcr cell lines, respectively. In the part of in vivo study, DMBA was used for inducing acute myeloid leukemia in mice. CdNPs similar to daunorubicin ameliorated significantly (p≤0.01) the biochemical, inflammatory, RBC, WBC, platelet, stereological, histopathological, and cellular-molecular parameters compared to the other groups.ConclusionsAs mentioned, the cadmium nanoparticles had significant anti-acute myeloid leukemia effects. After approving the above results in the clinical trial studies, these cadmium nanoparticles can be used as a chemotherapeutic drug to treat acute myeloid leukemia in humans.

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