BCR-ABL1 mediated miR-150 downregulation through MYC contributed to myeloid differentiation block and drug resistance in chronic myeloid leukemia.
BCR-ABL1 mediated miR-150 downregulation through MYC contributed to myeloid differentiation block and drug resistance in chronic myeloid leukemia.
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BCR-ABL1通过MYC介导的miR-150下调导致慢性髓样白血病中的髓样分化阻滞和耐药性。
DOI：
10.3324/haematol.2018.193086
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发表时间：
2018-12
期刊：
影响因子：
10.1
通讯作者：
Polakova KM
中科院分区：
文献类型：
--
作者：
Srutova K;Curik N;Burda P;Savvulidi F;Silvestri G;Trotta R;Klamova H;Pecherkova P;Sovova Z;Koblihova J;Stopka T;Perrotti D;Polakova KM
融合癌蛋白BCR-ABL 1表现出异常的酪氨酸激酶活性，并且已经提出它使涉及转录因子和非编码microRNA的信号网络失调，导致慢性髓性白血病（CML）。以前，microRNA表达谱显示CML中miR-150和miR-155的表达失调。在这项研究中，我们将这些发现置于MYC/miR-150/MYB/miR-155/PU.1致癌网络的更广泛背景下。我们认为，在CD 34+白血病干细胞和祖细胞中上调的MYC和miR-155与BCR-ABL 1一起损害了与低miR-150和PU.1水平相关的髓样分化的分子机制。我们发现MYC直接占据了MIR 150基因中的-11.7 kb和-0.35 kb调控区。通过BCR-ABL 1活性，MYC占据率显著增加，导致CML CD 34+和CD 34 −细胞中MIR 150基因表达抑制。此外，我们发现CML母细胞中miR-150水平降低与其对酪氨酸激酶抑制剂（TKI）的耐药性之间存在关联。虽然TKI成功地破坏了增殖的CML细胞中的BCR-ABL 1激酶活性，但这种治疗不能有效地靶向静止的白血病干细胞。该研究提供了关于由异常BCR-ABL 1活性建立的MYC/miR-150/MYB/miR-155/PU.1白血病网络的新证据。该网络的关键连接节点可能作为潜在的药物靶点，以克服CML干细胞和祖细胞的耐药性。
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.
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DOI：
10.3324/haematol.2009.020636
发表时间：
2010-08-01
期刊：
HAEMATOLOGICA-THE HEMATOLOGY JOURNAL
影响因子：
--
作者：
Flamant, Stephane;Ritchie, William;Rasko, John E. J.
通讯作者：
Rasko, John E. J.
影响因子：
11.4
作者：
Narayan, N.;Morenos, L.;Ekert, P. G.
通讯作者：
Ekert, P. G.
影响因子：
7.3
作者：
Hornick, Noah I.;Doron, Ben;Kurre, Peter
通讯作者：
Kurre, Peter
影响因子：
5.2
作者：
Pellicano, Francesca;Scott, Mary T.;Helgason, G. Vignir;Hopcroft, Lisa E. M.;Allan, Elaine K.;Aspinall-O'Dea, Mark;Copland, Mhairi;Pierce, Andrew;Huntly, Brian J. P.;Whetton, Anthony D.;Holyoake, Tessa L.
通讯作者：
Holyoake, Tessa L.
影响因子：
11.2
作者：
Adams CM;Hiebert SW;Eischen CM
通讯作者：
Eischen CM