Busch, Caroline and Mulholland, Theresa and Zagnoni, Michele and Dalby, Matthew and Berry, Catherine and Wheadon, Helen (2023) Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach. Cell Communication and Signaling, 21: 342. ISSN 1478-811X
AI Summary:
Targeting SRC, ABL and ALK kinases is more effective than ABL inhibition alone in combating chronic myeloid leukemia (CML) stem cell persistence. The combination efficacy was demonstrated in both 2D and 3D cell cultures.AI Topics:
Background:
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.
Methods:
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.
Results:
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.
Conclusion:
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.
Busch, Caroline
Author
Busch, Caroline and Nyamondo, Kudzai and Wheadon, Helen (2024) Complexities of modelling the bone marrow microenvironment to facilitate haematopoietic research. Experimental Hematology, 135: 104233. ISSN 0301-472X
Busch, Caroline and Mulholland, Theresa and Zagnoni, Michele and Dalby, Matthew and Berry, Catherine and Wheadon, Helen (2023) Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach. Cell Communication and Signaling, 21: 342. ISSN 1478-811X
See full publications listMulholland, Theresa
Author
Busch, Caroline and Mulholland, Theresa and Zagnoni, Michele and Dalby, Matthew and Berry, Catherine and Wheadon, Helen (2023) Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach. Cell Communication and Signaling, 21: 342. ISSN 1478-811X
See full publications listZagnoni, Michele
Author
Busch, Caroline and Mulholland, Theresa and Zagnoni, Michele and Dalby, Matthew and Berry, Catherine and Wheadon, Helen (2023) Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach. Cell Communication and Signaling, 21: 342. ISSN 1478-811X
See full publications listDalby, Matthew J.
Author
Cuahtecontzi Delint, Rosalia and Ishak, Mohd I. and Tsimbouri, Penelope M. and Jayawarna, Vineetha and Burgess, Karl V.E. and Ramage, Gordon and Nobbs, Angela H. and Damiati, Laila and Salmeron-Sanchez, Manuel and Su, Bo and Dalby, Matthew (2024) Nanotopography influences host-pathogen quorum sensing and facilitates selection of bioactive metabolites in mesenchymal stromal cells and pseudomonas aeruginosa co-cultures. ACS Applied Materials and Interfaces, 16 (33). pp. 43374-43386. ISSN 1944-8244
Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723
Doherty-Boyd, W. Sebastian and Tsimbouri, Monica P. and Donnelly, Hannah and Dalby, Matthew J. (2024) Building bones for blood and beyond: the growing field of bone marrow niche model development. Experimental Hematology, 135: 104232. ISSN 0301-472X
See full publications listBerry, Catherine
Author
Busch, Caroline and Mulholland, Theresa and Zagnoni, Michele and Dalby, Matthew and Berry, Catherine and Wheadon, Helen (2023) Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukaemia using a multi-kinase targeting approach. Cell Communication and Signaling, 21: 342. ISSN 1478-811X
See full publications listWheadon, Helen
Author
Donnelly, Hannah and Ross, Ewan and Xiao, Yinbo and Hermantara, Rio and Taqi, Aqeel and Doherty-Boyd, W. Sebastian and Cassels, Jennifer and Tsimbouri, Penelope M. and Dunne, Karen M. and Hay, Jodie and Cheng, Annie and Meek, R.M. Dominic and Jain, Nikhil and West, Christopher and Wheadon, Helen and Michie, Alison M. and Peault, Bruno and West, Adam G. and Salmeron-Sanchez, Manuel and Dalby, Matthew J. (2024) Bioengineered niches that recreate physiological extracellular matrix organisation to support long-term haematopoietic stem cells. Nature Communications, 15: 5791. ISSN 2041-1723
Busch, Caroline and Nyamondo, Kudzai and Wheadon, Helen (2024) Complexities of modelling the bone marrow microenvironment to facilitate haematopoietic research. Experimental Hematology, 135: 104233. ISSN 0301-472X
Dawson, Amy and Zarou, Martha M. and Prasad, Bodhayan and Bittencourt-Silvestre, Joana and Zerbst, Désirée and Himonas, Ekaterini and Hsieh, Ya-Ching and van Loon, Isabel and Rodriguez Blanco, Giovanny and Ianniciello, Angela and Kerekes, Zsombor and Krishnan, Vaidehi and Agarwal, Puneet and Almasoudi, Hassan and McCluskey, Laura and Hopcroft, Lisa E.M. and Scott, Mary T. and Baquero, Pablo and Dunn, Karen and Vetrie, David and Copland, Mhairi and Bhatia, Ravi and Coffelt, Seth B. and Tiong, Ong Sin and Wheadon, Helen and Zanivan, Sara and Kirschner, Kristina and Helgason, G. Vignir (2024) Leukaemia exposure alters the transcriptional profile and function of BCR::ABL1 negative macrophages in the bone marrow niche. Nature Communications, 15: 1090. ISSN 2041-1723
See full publications listAvailable under License Creative Commons Attribution.
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