Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach.
Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach.
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DOI：
10.1186/s12964-023-01363-2
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发表时间：
2023-11-29
影响因子：
8.4
通讯作者：
Wheadon, Helen
中科院分区：
文献类型：
--
作者：
Busch, Caroline;Mulholland, Theresa;Zagnoni, Michele;Dalby, Matthew;Berry, Catherine;Wheadon, Helen
关键词：
尽管使用酪氨酸激酶抑制剂（TKI）改善了患者结局，但由于白血病干细胞（LSC）持续存在，慢性髓性白血病（CML）患者需要终身治疗。LSC位于骨髓（BM）龛中，它们对其进行修饰以获得优势。BM提供癌基因非依赖性信号以帮助LSC细胞存活和静止。骨形态发生途径（BMP）是一种在CML中被鉴定为高度失调的途径，在BM中检测到高水平的BMP配体，伴随着CML干细胞和祖细胞过度表达BMP 1型受体-激活素样激酶（ALK），尤其是在TKI耐药患者中。Saracatinib（SC）是一种SRC/ABL 1双重抑制剂，可抑制对TKI伊马替尼（IM）耐药的CML细胞的生长。最近的研究表明，SC也是一种有效的ALK抑制剂和BMP拮抗剂。在这里，我们研究了SC在2D和3D培养中克服CML BCR：：ABL 1依赖性和非依赖性BM小生境介导的信号的功效。CML细胞（K562细胞系和CML CD 34+原代细胞）用IM、SC和BMP受体抑制剂dorsomorphin（DOR）的单一或组合处理进行处理，在AggreWell和微流体装置中在HS 5基质细胞系和间充质干细胞上在2D（悬浮液）和3D共培养中有或没有BMP 4刺激。进行流式细胞术以研究细胞凋亡、细胞周期进展和增殖，以及处理后的集落测定。通过免疫印迹和Fluidigm多重qPCR验证蛋白质变化和转录变化。通过靶向BMP通路，使用针对ALK的特异性抑制剂与SRC和ABL TKI组合，我们显示细胞凋亡增加，细胞周期调节改变，细胞分裂减少，CD 34+细胞数量减少。联合治疗后也发生了长期增殖和分化潜力的损害。BMP信号通路对于CML细胞存活是重要的。靶向SRC、ABL和ALK激酶比单独抑制ABL更有效，在2D和3D细胞培养物中证明了联合疗效，这突出了与标准治疗单一药物相比对联合治疗的需求。我们的研究为靶向CML中的多种激酶以对抗LSC持续性提供了依据。在线版本包含补充材料，可通过10.1186/s12964-023-01363-2获得。血液是在骨头最里面的海绵状部分，称为骨髓中产生的。骨髓是正常的造血干细胞生活的地方，负责产生不同的血细胞类型;白色血细胞（抗感染），红细胞（携带氧气在身体周围），血小板（凝血）和其他细胞支持这一过程。慢性粒细胞白血病（CML）是一种始于骨髓的血液癌症。CML发生时，正常的血液干细胞受损，形成白血病干细胞（LSC），导致血癌。LSC繁殖并产生许多不能正常工作的有缺陷的癌性白色血细胞。患者接受一种名为伊马替尼的药物治疗，这种药物可以减少体内循环的癌细胞数量。在许多情况下，这种治疗不足以治愈疾病，因为骨髓保护LSC免受药物的影响，这意味着患者必须长期接受治疗。这项工作发现了骨髓保护LSC免受治疗的方式之一，并利用这一知识来测试阻止这种保护的新药。我们的研究结果表明，通过结合两种药物，一种克服这种保护，另一种直接靶向癌细胞，我们可以摧毁更多的LSC。这些发现向治愈CML迈出了一步，并可能在未来改善患者的治疗。视频摘要在线版本包含补充材料，可通过10. 1186/s12964-023-01363-2获取。
Despite improved patient outcome using tyrosine kinase inhibitors (TKIs), chronic myeloid leukaemia (CML) patients require life-long treatment due to leukaemic stem cell (LSC) persistence. LSCs reside in the bone marrow (BM) niche, which they modify to their advantage. The BM provides oncogene-independent signals to aid LSC cell survival and quiescence. The bone-morphogenetic pathway (BMP) is one pathway identified to be highly deregulated in CML, with high levels of BMP ligands detected in the BM, accompanied by CML stem and progenitor cells overexpressing BMP type 1 receptors- activin-like kinases (ALKs), especially in TKI resistant patients. Saracatinib (SC), a SRC/ABL1 dual inhibitor, inhibits the growth of CML cells resistant to the TKI imatinib (IM). Recent studies indicate that SC is also a potent ALK inhibitor and BMP antagonist. Here we investigate the efficacy of SC in overcoming CML BCR::ABL1 dependent and independent signals mediated by the BM niche both in 2D and 3D culture. CML cells (K562 cell line and CML CD34+ primary cells) were treated with single or combination treatments of: IM, SC and the BMP receptors inhibitor dorsomorphin (DOR), with or without BMP4 stimulation in 2D (suspension) and 3D co-culture on HS5 stroma cell line and mesenchymal stem cells in AggreWell and microfluidic devices. Flow cytometry was performed to investigate apoptosis, cell cycle progression and proliferation, alongside colony assays following treatment. Proteins changes were validated by immunoblotting and transcriptional changes by Fluidigm multiplex qPCR. By targeting the BMP pathway, using specific inhibitors against ALKs in combination with SRC and ABL TKIs, we show an increase in apoptosis, altered cell cycle regulation, fewer cell divisions, and reduced numbers of CD34+ cells. Impairment of long-term proliferation and differentiation potential after combinatorial treatment also occurred. BMP signalling pathway is important for CML cell survival. Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone, the combination efficacy importantly being demonstrated in both 2D and 3D cell cultures highlighting the need for combinatorial therapies in contrast to standard of care single agents. Our study provides justification to target multiple kinases in CML to combat LSC persistence. The online version contains supplementary material available at 10.1186/s12964-023-01363-2. Blood is made in the spongy inner most section of the bone, called the bone marrow. The bone marrow is where normal blood stem cells live that are responsible for producing the different blood cell types; white blood cells (fight infections), red blood cells (carrying oxygen around the body), platelets (blood clotting) and other cells which support this process. Chronic myeloid leukaemia (CML) is a type of blood cancer that starts in the bone marrow. CML occurs when a normal blood stem cell becomes damaged, forming a leukaemia stem cell (LSC), leading to blood cancer. LSCs multiply and generate many faulty cancerous white blood cells that do not work properly. Patients are treated with a drug called imatinib, which reduces the number of cancerous cells circulating in the body. In many cases, this treatment is not enough to cure the disease because the bone marrow protects the LSCs from the drug meaning patients must remain on long term treatment. This work has discovered one of the ways in which the bone marrow protects LSCs from treatments and has used this knowledge to test new drugs that stop this protection. Our findings show that by combining two drugs, one that overcomes this protection and one that directly targets the cancerous cells, we can destroy more of the LSCs. These findings are a step closer towards a cure for CML and could improve treatment for patients in the future. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01363-2.
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影响因子：
20.3
作者：
Grockowiak, Elodie;Laperrousaz, Bastien;Maguer-Satta, Veronique
通讯作者：
Maguer-Satta, Veronique
影响因子：
5.2
作者：
Alves R;Gonçalves AC;Rutella S;Almeida AM;De Las Rivas J;Trougakos IP;Sarmento Ribeiro AB
通讯作者：
Sarmento Ribeiro AB
影响因子：
5
作者：
Azevedo, Pedro L.;Olivetra, Nathalia C. A.;Binato, Renate
通讯作者：
Binato, Renate
DOI：
10.1056/nejmoa1306494
发表时间：
2013-11-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Cortes JE;Kim DW;Pinilla-Ibarz J;le Coutre P;Paquette R;Chuah C;Nicolini FE;Apperley JF;Khoury HJ;Talpaz M;DiPersio J;DeAngelo DJ;Abruzzese E;Rea D;Baccarani M;Müller MC;Gambacorti-Passerini C;Wong S;Lustgarten S;Rivera VM;Clackson T;Turner CD;Haluska FG;Guilhot F;Deininger MW;Hochhaus A;Hughes T;Goldman JM;Shah NP;Kantarjian H;PACE Investigators
通讯作者：
PACE Investigators
慢性阶段的慢性髓样白血病的前线尼洛替尼与伊马替尼的长期益处和风险：随机ENESTND试验的5年更新。
影响因子：
11.4
作者：
Hochhaus A;Saglio G;Hughes TP;Larson RA;Kim DW;Issaragrisil S;le Coutre PD;Etienne G;Dorlhiac-Llacer PE;Clark RE;Flinn IW;Nakamae H;Donohue B;Deng W;Dalal D;Menssen HD;Kantarjian HM
通讯作者：
Kantarjian HM