The fusion oncoprotein BCR-ABL1 exhibits aberrant tyrosine kinase activity and it has been proposed that it deregulates signaling networks involving both transcription factors and non-coding microRNAs that result in chronic myeloid leukemia (CML). Previously, microRNA expression profiling showed deregulated expression of miR-150 and miR-155 in CML. In this study, we placed these findings into the broader context of the MYC/miR-150/MYB/miR-155/PU.1 oncogenic network. We propose that up-regulated MYC and miR-155 in CD34+ leukemic stem and progenitor cells, in concert with BCR-ABL1, impair the molecular mechanisms of myeloid differentiation associated with low miR-150 and PU.1 levels. We revealed that MYC directly occupied the -11.7 kb and -0.35 kb regulatory regions in the MIR150 gene. MYC occupancy was markedly increased through BCR-ABL1 activity, causing inhibition of MIR150 gene expression in CML CD34+ and CD34- cells. Furthermore, we found an association between reduced miR-150 levels in CML blast cells and their resistance to tyrosine kinase inhibitors (TKIs). Although TKIs successfully disrupted BCR-ABL1 kinase activity in proliferating CML cells, this treatment did not efficiently target quiescent leukemic stem cells. The study presents new evidence regarding the MYC/miR-150/MYB/miR-155/PU.1 leukemic network established by aberrant BCR-ABL1 activity. The key connecting nodes of this network may serve as potential druggable targets to overcome resistance of CML stem and progenitor cells.

• MeSH
• bcr-abl fúzní proteiny genetika   MeSH
• buněčná diferenciace účinky léků   genetika   MeSH
• buňky K562 MeSH
• chemorezistence účinky léků   genetika   MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   patologie   MeSH
• dospělí MeSH
• down regulace účinky léků   MeSH
• geny myc genetika   MeSH
• HL-60 buňky MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mikro RNA genetika   MeSH
• nádorové buněčné linie MeSH
• nádorové kmenové buňky účinky léků   metabolismus   MeSH
• proliferace buněk účinky léků   genetika   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• inhibitory proteinkinas MeSH
• mikro RNA MeSH
• MIRN150 microRNA, human MeSH Prohlížeč

The transcription factor c-Myb is required for modulation of progenitor cells in several tissues, including skeletal muscle and its upregulation is observed in many human malignancies. Rhabdomyosarcomas (RMS) are a heterogeneous group of mesodermal tumors with features of developing skeletal muscle. Several miRNAs are downregulated in RMS, including miR-150, a negative regulator of c-Myb expression. Using the C2C12 myoblast cell line, a cellular model of skeletal muscle differentiation, we showed that miR-150 controls c-Myb expression mainly at the level of translation. We hypothesized that a similar mechanism of c-Myb regulation operates in RMS tumors. We examined expression of c-Myb by immunohistochemistry and revealed c-Myb positivity in alveolar and embryonal tumors, the two most common subgroups of RMS. Furthermore, we showed direct correlation between c-Myb production and myogenin expression. Interestingly, high myogenin levels indicate poor prognosis in RMS patients. c-Myb could, therefore, contribute to the tumor phenotype by executing its inhibitory role in skeletal muscle differentiation. We also showed that c-Myb protein is abundant in migratory C2C12 myoblasts and its ectopic expression potentiates cell motility. In summary, our results implicate that metastatic properties of some RMS subtypes might be linked to c-Myb function.

• MeSH
• lidé MeSH
• myogenin MeSH
• myši MeSH
• nádorové biomarkery metabolismus   MeSH
• nádorové buněčné linie MeSH
• protoonkogenní proteiny c-myb metabolismus   MeSH
• regulace genové exprese u nádorů * MeSH
• rhabdomyosarkom metabolismus   patologie   sekundární   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• myogenin MeSH
• nádorové biomarkery MeSH
• protoonkogenní proteiny c-myb MeSH

The efficacy of therapeutic modalities in chronic myeloid leukemia (CML) depends on both genetic and epigenetic mechanisms. This review focuses on epigenetic mechanisms involved in the pathogenesis of CML and in resistance of tumor cells to tyrosine kinase inhibitors leading to the leukemic clone escape and propagation. Regulatory events at the levels of gene regulation by transcription factors and microRNAs are discussed in the context of CML pathogenesis and therapeutic modalities.

• MeSH
• bcr-abl fúzní proteiny antagonisté a inhibitory   genetika   terapeutické užití   MeSH
• chemorezistence MeSH
• chronická myeloidní leukemie farmakoterapie   genetika   patologie   MeSH
• epigenomika * MeSH
• inhibitory proteinkinas farmakologie   terapeutické užití   MeSH
• lidé MeSH
• metylace DNA MeSH
• mikro RNA fyziologie   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• regulace genové exprese u leukemie účinky léků   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• bcr-abl fúzní proteiny MeSH
• inhibitory proteinkinas MeSH
• mikro RNA MeSH
• protinádorové látky MeSH