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

Rothe, Katharina; Babaian, Artem; Nakamichi, Naoto; Chen, Min; Chafe, Shawn C.; Watanabe, Akie; Forrest, Donna L.; Mager, Dixie L.; Eaves, Connie J.; Dedhar, Shoukat; Jiang, Xiaoyan

doi:10.1016/j.stem.2020.04.005

Cited by 31 publications

(28 citation statements)

References 69 publications

(89 reference statements)

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“…Regarding regulation of the tricarboxylic acid (TCA) cycle and OxPHOS, a comparative gene expression analysis in CML stem-progenitor cells isolated from TKI-responding and non-responding patients revealed upregulation of ILK (integrin-linked kinase) in LSCs of non-responding patients [ 152 ]. It was shown that ILK regulates quiescence of non-responding LSCs through the OxPHOS pathway [ 152 ]. The multifunctional sirtuin 1 (SIRT1) was also found to be induced in CML-LSCs and contributes to their resistance to TKIs [ 153 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

“…Kumar et al (2020) showed that BCR-ABL1 T315I mutated cells presented alteration in the actin cytoskeleton, integrin β3 levels, in the expression and phosphorylation levels of FAK and ILK, and fibronectin expression when compared with BCR-ABL1 sensitive cells [ 194 ]. In CML, the increased expression of integrin β3 and ILK interaction with β integrins was associated with Imatinib resistance through the activation of PI3K/AKT, STAT3, and ERK1/2 signaling pathways [ 152 ]. Furthermore, the interaction with MSCs can also be mediated by N-cadherin and the activation of β-catenin signaling, which are crucial for LSC [ 195 ].…”

Section: Molecular Mechanismsmentioning

confidence: 99%

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Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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Section: Molecular Mechanismsmentioning

confidence: 99%

Section: Molecular Mechanismsmentioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

View full text Add to dashboard Cite

show abstract

“…Importantly, GSEA indicated that QLT0267 repressed expression of mitochondrial OXPHOS-related genes in quiescent CML stem cells. These data establish that ILK has a critical function in regulating the quiescence of TKI-insensitive CML stem cells through the OXPHOS pathway [25].…”

Section: Ilkmentioning

confidence: 53%

“…Rothe et al compared gene expression profiles between human CML stem/progenitor cells isolated from TKIresponder and TKI-non-responder patients, and found that ILK (Integrin-linked kinase) mRNA was elevated in TKIinsensitive CML stem/progenitor cells compared to TKIsensitive CML stem/progenitor cells [25]. To understand the functional role of ILK, they introduced shRNA targeting ILK mRNA into CML stem/progenitor cells from CP-CML patients, and transplanted these ILK-shRNA-transduced CML stem/progenitor cells into immunodeficient NRG mice.…”

Section: Ilkmentioning

confidence: 99%

New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism

Naka

2021

Int J Hematol

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Chronic myelogenous leukemia (CML) stem cells are the cellular source of the vast majority of mature CML cells and responsible for relapse of CML disease post-tyrosine kinase inhibitor (TKI) therapy. Although mature CML cells, whose active division is driven by BCR-ABL1 oncogene-dependent signaling, are reduced by TKI therapy, CML stem cells are resistant because they become quiescent via a heretofore elusive mechanism that is independent of oncogene signaling. Recent advances in highly sensitive metabolomics analyses, however, have unveiled new metabolic pathways that are essential for the survival of CML stem cells. With respect to glucose metabolism, CML stem cells elevate anaplerosis to sustain the TCA cycle. Blast crisis (BC)-CML stem cells increase their branched-chained amino acid (BCAA) metabolism. Recently, we showed that CML stem cell quiescence in vivo is regulated by lysophospholipid metabolism that is specific to these cells, namely cooperation between the stemness factors FOXO and β-catenin. These findings reveal biologically significant links between CML stemness and novel metabolic mechanisms. In this review, I describe these links in the contexts of glucose, amino acid, and lipid metabolism, and speculate on how innovative therapeutics might be designed to eradicate CML stem cells in vivo and overcome disease relapse post-TKI therapy.

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“…Even the second generation TKIs nilotinib and dasatinib are not effective at eradicating quiescent CML LSCs 15,16 . CML LSCs share many features with normal HSCs, such as the quiescent state, localization in the hypoxia niche, and selfrenewal ability 17,18,19,20,21 . Their quiescent state is one of the major reasons why CML LSCs are resistant to BCR-ABL1 TKIs 22,23 .…”

Section: Introductionmentioning

confidence: 99%

Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Tanaka¹,

Mikami²,

Tsuchiya³

et al. 2021

Preprint

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Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a novel G0 marker (G0M), we narrowed down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis revealed NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by IRAK1/4 inhibitors together with imatinib eradicated mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuated PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eradicated CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors could eradicate CML LSCs through inhibiting NF-ΚB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML.

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

Cited by 31 publications

References 69 publications

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

New routes to eradicating chronic myelogenous leukemia stem cells by targeting metabolism

Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

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