Investigation of the Effects of STAT5 Inhibitor Pimozide Treatment on Chemosensitivity and Leukemogenesis in Tyrosine Kinase Inhibitor-Responsive and -Resistant CML Stem Cells

Project no. 30805 · Status: Kapanmış (Yayın bekleniyor) · 2023

Summary

<p>Chronic&nbsp;myeloid&nbsp;leukemia&nbsp;(CML),&nbsp;a&nbsp;clonal&nbsp;myeloproliferative&nbsp;disorder&nbsp;arising&nbsp;from&nbsp;haematopoietic&nbsp;stem&nbsp;cells&nbsp;and&nbsp;transformed&nbsp;haematopoietic&nbsp;progenitor&nbsp;cells,&nbsp;is&nbsp;characterised&nbsp;by&nbsp;the&nbsp;Philadelphia&nbsp;chromosome,&nbsp;which&nbsp;encodes&nbsp;the&nbsp;BCR::ABL1&nbsp;fusion&nbsp;oncoprotein&nbsp;resulting&nbsp;from&nbsp;t(9;22)(q34;q11.2).&nbsp;This&nbsp;oncoprotein&nbsp;promotes&nbsp;the&nbsp;survival&nbsp;of&nbsp;leukemic&nbsp;cells&nbsp;by&nbsp;providing&nbsp;a&nbsp;continuous&nbsp;proliferation&nbsp;signal&nbsp;due&nbsp;to&nbsp;increased&nbsp;tyrosine&nbsp;kinase&nbsp;activity.&nbsp;Targeting&nbsp;this&nbsp;oncoprotein&nbsp;with&nbsp;tyrosine&nbsp;kinase&nbsp;inhibitors&nbsp;(TKIs)&nbsp;has&nbsp;ushered&nbsp;in&nbsp;a&nbsp;new&nbsp;era&nbsp;in&nbsp;CML&nbsp;treatment.&nbsp;Loss&nbsp;of&nbsp;response&nbsp;due&nbsp;to&nbsp;the&nbsp;development&nbsp;of&nbsp;resistance&nbsp;to&nbsp;the&nbsp;first-line&nbsp;TKI&nbsp;imatinib&nbsp;is&nbsp;a&nbsp;significant&nbsp;public&nbsp;health&nbsp;problem&nbsp;that&nbsp;needs&nbsp;to&nbsp;be&nbsp;addressed.&nbsp;Therefore,&nbsp;identifying&nbsp;new&nbsp;agents&nbsp;or&nbsp;combination&nbsp;therapies&nbsp;targeting&nbsp;oncogenic&nbsp;signalling&nbsp;pathways&nbsp;is&nbsp;an&nbsp;important&nbsp;therapeutic&nbsp;strategy&nbsp;to&nbsp;overcome&nbsp;chemotherapeutic&nbsp;resistance&nbsp;in&nbsp;CML&nbsp;treatment.&nbsp;As&nbsp;STAT&nbsp;transcription&nbsp;factors&nbsp;are&nbsp;targets&nbsp;of&nbsp;numerous&nbsp;tyrosine&nbsp;kinases,&nbsp;they&nbsp;have&nbsp;the&nbsp;potential&nbsp;to&nbsp;serve&nbsp;as&nbsp;a&nbsp;therapeutic&nbsp;approach&nbsp;for&nbsp;overcoming&nbsp;TKI&nbsp;resistance.&nbsp;Since&nbsp;STAT5&nbsp;signalling&nbsp;is&nbsp;a&nbsp;critical&nbsp;mediator&nbsp;in&nbsp;the&nbsp;development&nbsp;of&nbsp;the&nbsp;CML&nbsp;phenotype,&nbsp;targeting&nbsp;a&nbsp;downstream&nbsp;mediator&nbsp;such&nbsp;as&nbsp;STAT5&nbsp;with&nbsp;an&nbsp;inhibitor&nbsp;to&nbsp;enable&nbsp;combination&nbsp;therapy&nbsp;is&nbsp;a&nbsp;strategic&nbsp;treatment&nbsp;approach.</p><p></p><p>This&nbsp;study,&nbsp;which&nbsp;preliminarily&nbsp;demonstrated&nbsp;that&nbsp;Pimozide&nbsp;has&nbsp;a&nbsp;high&nbsp;binding&nbsp;affinity&nbsp;for&nbsp;the&nbsp;active&nbsp;tyrosine&nbsp;kinase&nbsp;domain&nbsp;of&nbsp;BCR::ABL1&nbsp;through&nbsp;simulation-molecular&nbsp;docking&nbsp;analysis,&nbsp;suggests&nbsp;that&nbsp;the&nbsp;STAT5&nbsp;inhibitor&nbsp;Pimozide&nbsp;inhibits&nbsp;STAT5&nbsp;activation.&nbsp;In&nbsp;the&nbsp;K562&nbsp;cell&nbsp;line&nbsp;and&nbsp;its&nbsp;2&nbsp;µM-resistant&nbsp;form,&nbsp;the&nbsp;healthy&nbsp;lymphoblast&nbsp;cell&nbsp;line&nbsp;NCIBL2171,&nbsp;and&nbsp;haematopoietic&nbsp;stem&nbsp;cells&nbsp;(HSC),&nbsp;the&nbsp;potential&nbsp;synergistic&nbsp;effect&nbsp;of&nbsp;Imatinib&nbsp;and&nbsp;Pimozide&nbsp;combination&nbsp;therapy&nbsp;on&nbsp;leukemic&nbsp;cells,&nbsp;its&nbsp;apoptotic&nbsp;effect,&nbsp;the&nbsp;impact&nbsp;of&nbsp;the&nbsp;active&nbsp;ingredients&nbsp;on&nbsp;the&nbsp;migration&nbsp;properties&nbsp;of&nbsp;leukaemic&nbsp;cells,&nbsp;and&nbsp;the&nbsp;possible&nbsp;correlation&nbsp;between&nbsp;the&nbsp;retention&nbsp;phase&nbsp;observed&nbsp;in&nbsp;cell&nbsp;cycle&nbsp;arrest&nbsp;analysis&nbsp;and&nbsp;mRNA&nbsp;expression&nbsp;values&nbsp;were&nbsp;determined.</p><p></p><p>Thus,&nbsp;by&nbsp;defining&nbsp;the&nbsp;molecular&nbsp;targets&nbsp;of&nbsp;Pimozide&#39;s&nbsp;STAT5&nbsp;inhibitory&nbsp;effect,&nbsp;a&nbsp;significant&nbsp;contribution&nbsp;will&nbsp;be&nbsp;made&nbsp;to&nbsp;elucidating&nbsp;the&nbsp;mechanism&nbsp;of&nbsp;Imatinib&nbsp;resistance&nbsp;development.&nbsp;With&nbsp;this&nbsp;new&nbsp;anti-leukemic&nbsp;combination&nbsp;treatment&nbsp;strategy,&nbsp;it&nbsp;is&nbsp;thought&nbsp;that&nbsp;chemoresponsiveness&nbsp;to&nbsp;TKIs&nbsp;can&nbsp;be&nbsp;restored&nbsp;and&nbsp;resistance&nbsp;overcome.</p>

View details