Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

Kaehler, Meike; Cascorbi, Ingolf

doi:10.1007/164_2023_639

Cited by 4 publications

(5 citation statements)

References 134 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Genomic instability leads to the accumulation of mutations at the ABL KD and other molecular or chromosomal aberrations. Vice versa, overexpression of BCR-ABL fusion proteins can also lead to genomic instability in CML cells 20 . Partial deletions of RUNX1 and PMRD16 , expression of RUNX1/PMRD16 , and mutations in GATA2 activation are also associated with CML progression and their presence may be detected in CML 14 , 35 .…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…Novicki et al have demonstrated that HR and NHEJ are enhanced in ROS-mediated DSB repair in BCR-ABL cells, where these mechanisms lead to mutations and a large number of deletions. In fact, BCR-ABL (non-mutant and T315I mutants) has been shown to bind and phosphorylate RAD51 and its paralog RAD51B, promoting unfaithful homologous HR in a dose-dependent manner 20 .…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…Overexpression of SRC family kinase proteins, such as LYN and HCK, is essential for cell proliferation, survival, and adhesion 19 , 20 . SRC proteins lead to AKT activation and promote survival and STAT5 activation to stimulate proliferation.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…GAB2 is a member of the GAB family of docking proteins that play a key role in CML by amplifying BCR-ABL signaling. Dysregulation of this protein leads to increased proliferation, decreased demand for growth factors, and increased cell viability 20 . In addition, continuous phosphorylation of GAB2 leads to activation of substrates, such as the stabilization of RAS proteins in active form after GAB2 activation.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

“…Point mutations in the BCR-ABL fusion gene are the most common cause of TKI resistance, with about 31%-63% of imatinib (IM) resistance attributed to point mutations [19][20][21]. According to the published literature, more than 100 mutations have been found, distributed in the ABL amino acid range of 220-500 (Figure 2) [19].…”

Section: Bcr-abl Kinase Domain Mutationsmentioning

confidence: 99%

See 4 more Smart Citations

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

Sun,

Hu,

Han

et al. 2024

Int. J. Biol. Sci.

View full text Add to dashboard Cite

Chronic myeloid leukemia (CML) is a malignant clonal disease involving hematopoietic stem cells that is characterized by myeloid cell proliferation in bone marrow and peripheral blood, and the presence of the Philadelphia (Ph) chromosome with BCR-ABL fusion gene. Treatment of CML has dramatically improved since the advent of tyrosine kinase inhibitors (TKI). However, there are a small subset of CML patients who develop resistance to TKI. Mutations in the ABL kinase domain (KD) are currently recognized as the leading cause of TKI resistance in CML. In this review, we discuss the concept of resistance and summarize recent advances exploring the mechanisms underlying CML resistance. Overcoming TKI resistance appears to be the most successful approach to reduce the burden of leukemia and enhance cures for CML. Advances in new strategies to combat drug resistance may rapidly change the management of TKI-resistant CML and expand the prospects for available therapies.

show abstract

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Section: Bcr-abl Kinase Domain Mutationsmentioning

confidence: 99%

See 3 more Smart Citations

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

Sun,

Hu,

Han

et al. 2024

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

PRMT1 Promotes the Self‐renewal of Leukemia Stem Cells by Regulating Protein Synthesis

Zhou,

Huang,

et al. 2024

Advanced Science

View full text Add to dashboard Cite

The application of tyrosine kinase inhibitors (TKIs) has revolutionized the management of chronic myeloid leukemia (CML). However, disease relapse and progression particularly due to persistent leukemia stem cells (LSCs) remain a big challenge in the clinic. Therefore, validation of the therapeutic vulnerability in LSCs is urgently needed. This study verifies the critical role of protein arginine methyltransferase 1 (PRMT1) in the maintenance of CML LSCs. It is found that PRMT1 promotes the survival and serially plating abilities of human primary CML LSCs. Genetic deletion of Prmt1 significantly delays the leukemogenesis and impairs the self‐renewal of LSCs in BCR‐ABL–driven CML mice. PRMT1 regulates LSCs and leukemia development depending on its methyltransferase activity. Pharmacological inhibition of PRMT1 activity by MS023 remarkably eliminates LSCs and prolongs the survival of CML mice. Mechanistical studies reveal that PRMT1 promotes transcriptional activation of ribosomal protein L29 (RPL29) via catalyzing asymmetric dimethylation of histone H4R3 (H4R3me2a) at its gene promoter region. PRMT1 augments the global protein synthesis via RPL29 in CML LSCs. Taken together, the findings provide new evidence that histone arginine methylation modification regulates protein synthesis in LSCs and highlight PRMT1 as a valuable druggable target for patients with CML.

show abstract

Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms

Kaehler,

von Bubnoff,

Cascorbi

et al. 2024

Front. Pharmacol.

View full text Add to dashboard Cite

Leukemia represents a diverse group of hematopoietic neoplasms that can be classified into different subtypes based on the molecular aberration in the affected cell population. Identification of these molecular classification is required to identify specific targeted therapeutic approaches for each leukemic subtype. In general, targeted therapy approaches achieve good responses in some leukemia subgroups, however, resistance against these targeted therapies is common. In this review, we summarize molecular drug resistance biomarkers in targeted therapies in BCR::ABL1-driven chronic myeloid leukemia (CML) and JAK2-driven myeloproliferative neoplasms (MPNs). While acquisition of secondary mutations in the BCR::ABL1 kinase domain is the a common mechanism associated with TKI resistance in CML, in JAK2-driven MPNs secondary mutations in JAK2 are rare. Due to high prevalence and lack of specific therapy approaches in MPNs compared to CML, identification of crucial pathways leading to inhibitor persistence in MPN model is utterly important. In this review, we focus on different alternative signaling pathways activated in both, BCR::ABL1-mediated CML and JAK2-mediated MPNs, by combining data from in vitro and in vivo-studies that could be used as potential biomarkers of drug resistance. In a nutshell, some common similarities, especially activation of PDGFR, Ras, PI3K/Akt signaling pathways, have been demonstrated in both leukemias. In addition, induction of the nucleoprotein YBX1 was shown to be involved in TKI-resistant JAK2-mediated MPN, as well as TKI-resistant CML highlighting deubiquitinating enzymes as potential biomarkers of TKI resistance. Taken together, whole exome sequencing of cell-based or patients-derived samples are highly beneficial to define specific resistance markers. Additionally, this might be helpful for the development of novel diagnostic tools, e.g., liquid biopsy, and novel therapeutic agents, which could be used to overcome TKI resistance in molecularly distinct leukemia subtypes.

show abstract

Molecular Mechanisms of Tyrosine Kinase Inhibitor Resistance in Chronic Myeloid Leukemia

Cited by 4 publications

References 134 publications

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

Mechanisms underlying therapeutic resistance of tyrosine kinase inhibitors in chronic myeloid leukemia

PRMT1 Promotes the Self‐renewal of Leukemia Stem Cells by Regulating Protein Synthesis

Molecular biomarkers of leukemia: convergence-based drug resistance mechanisms in chronic myeloid leukemia and myeloproliferative neoplasms

Contact Info

Product

Resources

About