BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

Piwocka, Katarzyna; Wolanin, Kamila; Kusio-Kobiałka, Monika; Podszywałow-Bartnicka, Paulina

doi:10.5772/25780

Cited by 2 publications

(4 citation statements)

References 159 publications

(129 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We suggested before that BRCA1 protein downregulation in 32D cells expressing BCR-ABL1 was not a result of its increased degradation. 5 To confirm this observation we treated mouse cells expressing BCR-ABL1, human K562 cells as well as CD34 C primary cells from CML patient with proteasome inhibitor MG132 (Fig. 1C).…”

Section: Resultsmentioning

confidence: 70%

“…3 Recently we also reported that BRCA1-dependent defects in DSB repair in CML cells can sensitize them to synthetic lethality induced by RAD52 inhibitor. 6 BCR-ABL1-mediated downregulation of BRCA1 protein was not due to decreased BRCA1 mRNA expression and protein halflife, 5,6 and it was partially reversible by inhibition of BCR-ABL1 kinase by imatinib. 3,4 In addition, mutations abrogating the expression of BRCA1 protein have not been reported in CML.…”

Section: Introductionmentioning

confidence: 98%

“…4,5,6 In addition to HRR, BRCA1 protein has been implicated in a broad range of cellular processes, including cell cycle control, cell division and gene transcription. 7,8 We reported that downregulation of BRCA1 protein affected the function of spindle assembly checkpoint (SAC) and postmitotic checkpoint leading to aneuploidy and resistance to spindle poisons in CML cells.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation

Podszywałow-Bartnicka

Wolczyk

Kusio-Kobiałka

et al. 2014

Cell Cycle

Self Cite

View full text Add to dashboard Cite

BRCA1 tumor suppressor regulates crucial cellular processes involved in DNA damage repair and cell cycle control. We showed that expression of BCR-ABL1 correlates with decreased level of BRCA1 protein, which promoted aberrant mitoses and aneuploidy as well as altered DNA damage response. Using polysome profiling and luciferase-BRCA1 3'UTR reporter system here we demonstrate that downregulation of BRCA1 protein in CML is caused by inhibition of BRCA1 mRNA translation, but not by increased protein degradation or reduction of mRNA level and half-life. We investigated 2 mRNA-binding proteins -HuR and TIAR showing specificity to AU-Rich Element (ARE) sites in 3'UTR of mRNA. BCR-ABL1 promoted cytosolic localization of TIAR and HuR, their binding to BRCA1 mRNA and formation of the TIAR-HuR complex. HuR protein positively regulated BRCA1 mRNA stability and translation, conversely TIAR negatively regulated BRCA1 translation and was found localized predominantly in the cytosolic stress granules in CML cells. TIAR-dependent downregulation of BRCA1 protein level was a result of ER stress, which is activated in BCR-ABL1 expressing cells, as we previously shown. Silencing of TIAR in CML cells strongly elevated BRCA1 level. Altogether, we determined that TIARmediated repression of BRCA1 mRNA translation is responsible for downregulation of BRCA1 protein level in BCR-ABL1 -positive leukemia cells. This mechanism may contribute to genomic instability and provide justification for targeting PARP1 and/or RAD52 to induce synthetic lethality in "BRCAness" CML and BCR-ABL1 -positive ALL cells.

show abstract

Section: Resultsmentioning

confidence: 70%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation

Podszywałow-Bartnicka

Wolczyk

Kusio-Kobiałka

et al. 2014

Cell Cycle

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these cells, the usually faithful HRR induces point mutations, the NHEJ promotes extensive nucleobase loss, and the high activity of SSA generates large deletions [ 54 ]. Additionally, other DNA damage repair pathways are inhibited, including mismatch repair (MMR) and base excision repair (BER) [ 63 , 64 , 65 , 66 , 67 ], while the mutagenic nucleotide excision repair (NER) is promoted [ 68 ].…”

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

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.

show abstract

BCR-ABL Hits at Mitosis; Implications for Chromosomal Instability, Aneuploidy and Therapeutic Strategy

Cited by 2 publications

References 159 publications

Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation

Downregulation of BRCA1 protein in BCR-ABL1 leukemia cells depends on stress-triggered TIAR-mediated suppression of translation

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

Contact Info

Product

Resources

About