BCR and BCR-ABL regulation during myeloid differentiation in healthy donors and in chronic phase/blast crisis CML patients

Marega, M; Piazza, Rocco; Pirola, Alessandra; Redaelli, Sara; Mogavero, Angela; Iacobucci, Ilaria; Meneghetti, I; Parma, Matteo; Pogliani, Enrico Maria; Gambacorti‐Passerini, Carlo

doi:10.1038/leu.2010.101

Cited by 37 publications

(29 citation statements)

References 15 publications

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“…Therefore, we determined, by evaluating BCR promoter activity, if transcriptional activity was reduced in K562 under O 2 shortage (Figure 4B). BCR promoter controls the transcription of both BCR and BCR / abl genes [13]. K562 cells were incubated for 36 hours in low O 2 or under standard conditions and then ChIP-qPCR was performed to detect acetylated histone H4 at the BCR promoter.…”

Section: Resultsmentioning

confidence: 99%

Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction

et al. 2016

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BCR/Abl protein drives the onset and progression of Chronic Myeloid Leukemia (CML). We previously showed that BCR/Abl protein is suppressed in low oxygen, where viable cells retain stem cell potential. This study addressed the regulation of BCR/Abl protein expression under oxygen or glucose shortage, characteristic of the in vivo environment where cells resistant to tyrosine kinase inhibitors (TKi) persist. We investigated, at transcriptional, translational and post-translational level, the mechanisms involved in BCR/Abl suppression in K562 and KCL22 CML cells. BCR/abl mRNA steady-state analysis and ChIP-qPCR on BCR promoter revealed that BCR/abl transcriptional activity is reduced in K562 cells under oxygen shortage. The SUnSET assay showed an overall reduction of protein synthesis under oxygen/glucose shortage in both cell lines. However, only low oxygen decreased polysome-associated BCR/abl mRNA significantly in KCL22 cells, suggesting a decreased BCR/Abl translation. The proteasome inhibitor MG132 or the pan-caspase inhibitor z-VAD-fmk extended BCR/Abl expression under oxygen/glucose shortage in K562 cells. Glucose shortage induced autophagy-dependent BCR/Abl protein degradation in KCL22 cells. Overall, our results showed that energy restriction induces different cell-specific BCR/Abl protein suppression patterns, which represent a converging route to TKi-resistance of CML cells. Thus, the interference with BCR/Abl expression in environment-adapted CML cells may become a useful implement to current therapy.

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Section: Resultsmentioning

confidence: 99%

Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction

et al. 2016

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“…A number of studies have found increased expression of BCR-ABL1 in BC compared to CP. This increase was observed when comparing matched CP and BC samples (from the same patient) at both the mRNA [126][127][128][129] and protein levels [114,126,130]. Additionally, it has been shown that cells expressing higher amounts of BCR-ABL1 have an increase in genomic instability as well as perturbed differentiation, which are intrinsic properties of BC-CML [123,131].…”

Section: Bcr-abl1 and Bc-cmlmentioning

confidence: 99%

Natural course and biology of CML

2015

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Chronic myeloid leukaemia (CML) is a myeloproliferative disorder arising in the haemopoietic stem cell (HSC) compartment. This disease is characterised by a reciprocal t(9;22) chromosomal translocation, resulting in the formation of the Philadelphia (Ph) chromosome containing the BCR-ABL1 gene. As such, diagnosis and monitoring of disease involves detection of BCR-ABL1. It is the BCR-ABL1 protein, in particular its constitutively active tyrosine kinase activity, that forges the pathogenesis of CML. This aberrant kinase signalling activates downstream targets that reprogram the cell to cause uncontrolled proliferation and results in myeloid hyperplasia and 'indolent' symptoms of chronic phase (CP) CML. Without successful intervention, the disease will progress into blast crisis (BC), resembling an acute leukaemia. This advanced disease stage takes on an aggressive phenotype and is almost always fatal. The cell biology of CML is also centred on BCR-ABL1. The presence of BCR-ABL1 can explain virtually all the cellular features of the leukaemia (enhanced cell growth, inhibition of apoptosis, altered cell adhesion, growth factor independence, impaired genomic surveillance and differentiation). This article provides an overview of the clinical and cell biology of CML, and highlights key findings and unanswered questions essential for understanding this disease.

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“…The biological mechanism responsible for promoting the transition of CML from CP to BP is poorly understood. BCR-ABL promotes the development and progression of CML CP to BP [2, 3]. However, increasing studies have suggested that factors independent of BCR-ABL, including epigenetic modifiers, participate in CML-BP progression [4-6].…”

Section: Introductionmentioning

confidence: 99%

Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia

et al. 2014

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Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

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BCR and BCR-ABL regulation during myeloid differentiation in healthy donors and in chronic phase/blast crisis CML patients

Cited by 37 publications

References 15 publications

Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction

Different BCR/Abl protein suppression patterns as a converging trait of chronic myeloid leukemia cell adaptation to energy restriction

Natural course and biology of CML

Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia

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