Integrin-Linked Kinase Mediates Therapeutic Resistance of Quiescent CML Stem Cells to Tyrosine Kinase Inhibitors.

Integrin-Linked Kinase Mediates Therapeutic Resistance of Quiescent CML Stem Cells to Tyrosine Kinase Inhibitors. Cell Stem Cell. 2020 May 10;: Authors: Rothe K, Babaian A, Nakamichi N, Chen M, Chafe SC, Watanabe A, Forrest DL, Mager DL, Eaves CJ, Dedhar S, Jiang X Abstract Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role of ILK in maintaining a requisite level of mitochondrial oxidative metabolism in highly purified, quiescent LSCs. Thus, these findings point to ILK as a critical survival mediator to TKIs and quiescent stem cells, offering an attractive therapeutic target and model for curative combination therapies in stem-cell-driven cancers. PMID: 32413332 [PubMed - as supplied by publisher]
Source: Cell Stem Cell - Category: Stem Cells Authors: Tags: Cell Stem Cell Source Type: research

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Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/ Longevity Industry Consulting Services Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out m...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Contributor : Roman SasikSeries Type : Expression profiling by high throughput sequencingOrganism : Mus musculusWhile Chronic Myelogenous Leukemia (CML) is generally well controlled with Imatinib and other kinase inhibitors, blast crisis CML (bcCML) continues to be resistant to current therapies and remains highly lethal. Here we report a genome-wide in vivo CRISPR screen to better define the biological determinants of bcCML establishment and propagation in a physiologic context. This screen identified a large number of new genes and programs critically required for bcCML including those essential for chromatin remodeling,...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Mus musculus Source Type: research
Abstract New strategies to eradicate cancer stem cells in chronic myeloid leukemia (CML) include a combination of imatinib with peroxisome proliferator-activated receptor gamma (PPARγ) ligands. Recently, we identified the partial PPARγ agonist telmisartan as effective sensitizer of resistant K562 CML cells to imatinib treatment. Here, the importance of the heterocyclic core  on the cell death modulating effects  of the telmisartan-derived lead  4'-((2-propyl-1 H -benzo[ d ]imidazol-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid was investigated. Inspired by the  pharmacodynamics of ...
Source: ChemMedChem - Category: Chemistry Authors: Tags: ChemMedChem Source Type: research
Chronic myelogenous leukemia (CML) is a clonal myeloproliferative neoplasm resulting from BCR –ABL-transformed hematopoietic stem cells. Previous research has implicated multifunctional proinflammatory cytokine...
Source: Cancer Cell International - Category: Cancer & Oncology Authors: Tags: Primary research Source Type: research
Cancers, Vol. 12, Pages 318: HDAC6—an Emerging Target Against Chronic Myeloid Leukemia? Cancers doi: 10.3390/cancers12020318 Authors: Hélène Losson Michael Schnekenburger Mario Dicato Marc Diederich Imatinib became the standard treatment for chronic myeloid leukemia (CML) about 20 years ago, which was a major breakthrough in stabilizing the pathology and improving the quality of life of patients. However, the emergence of resistance to imatinib and other tyrosine kinase inhibitors leads researchers to characterize new therapeutic targets. Several studies have highlighted the role of histon...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
tsch JJ Abstract Chronic myeloid leukaemia (CML) is a clonal myeloproliferative stem cell disorder characterized by the constitutively active BCR-ABL tyrosine kinase. The LIM and SH3 domain protein 1 (LASP1) has recently been identified as a novel BCR-ABL substrate and is associated with proliferation, migration, tumorigenesis and chemoresistance in several cancers. Furthermore, LASP1 was shown to bind to the chemokine receptor 4 (CXCR4), thought to be involved in mechanisms of relapse. In order to identify potential LASP1-mediated pathways and related factors that may help to further eradicate minimal residual di...
Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
The anti-leukemia activity of NK cells helps prevent relapse during hematopoietic stem cell transplantation (HSCT) in leukemia patients. However, the factors that determine the sensitivity or resistance of leukemia cells in the context of NK-mediated cytotoxicity are not well-established. Here, we performed a genome-wide CRISPR screen in the human chronic-myelogenous-leukemia (CML) cell line K562 to identify genes that regulate the vulnerability of leukemia cells to killing by primary human NK cells. The distribution of guide RNAs (gRNAs) in K562 cells that survived co-incubation with NK cells showed that loss of NCR3LG1, ...
Source: Frontiers in Immunology - Category: Allergy & Immunology Source Type: research
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Source: Current Cancer Drug Targets - Category: Cancer & Oncology Authors: Tags: Curr Cancer Drug Targets Source Type: research
Authors: Malhotra H, Radich J, Garcia-Gonzalez P Abstract Subsequent to the development and global availability of BCR/ABL-targeted tyrosine kinase inhibitors (TKIs), the prognosis of patients with chronic myeloid leukemia (CML), at least those in the chronic phase, has markedly improved, and in the developed world, the average lifespan of these patients is now close to that of age- and sex-matched subjects without the disease. However, the situation in low- and middle-income countries (LMICs) may not be so rosy. Many important differences in hematological cancers, including CML, have been highlighted in various pu...
Source: Hematology ASH Education Program - Category: Hematology Tags: Hematology Am Soc Hematol Educ Program Source Type: research
Abstract The mammalian target of rapamycin (mTOR) inhibitor, DNA damage inducible transcript 4 (DDIT4), has inducible expression in response to various cellular stresses. In multiple malignancies, studies have shown that DDIT4 participates in tumorigenesis and impacts patient survival. We aimed to study the prognostic value of DDIT4 in acute myeloid leukaemia (AML), which is currently unclear. Firstly, The Cancer Genome Atlas was screened for AML patients with complete clinical characteristics and DDIT4 expression data. A total of 155 patients were included and stratified according to the treatment modality and th...
Source: J Cell Mol Med - Category: Molecular Biology Authors: Tags: J Cell Mol Med Source Type: research
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