Interleukin‐3‐mediated regulation of β‐catenin in myeloid transformation and acute myeloid leukemia

Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society

关键词: Hox;    gene‐;    expression profiling;    leukemic stem cell;   

DOI  :  10.1189/jlb.2AB1013-559R

学科分类：生理学

来源: Federation of American Societies for Experimental Biology

【 摘 要 】

Aberrantactivationofβ‐cateninisacommoneventinAMLandisanindependentpredictorofpoorprognosis.Althoughincreasedβ‐cateninsignalinginAMLhasbeenassociatedwithoncogenictranslocationproductsandactivatingmutationsintheFLT3R,themechanismsthatactivateβ‐catenininAMLmorebroadlyarestillunclear.Here,wedescribeanovellinkbetweenIL‐3signalingandtheregulationofβ‐catenininmyeloidtransformationandAML.InamurinemodelofHoxB8andIL‐3cooperation,weshowthatβ‐cateninproteinlevelsaremodulatedbyIL‐3andthatCre‐induceddeletionofβ‐cateninabolishesIL‐3‐dependentgrowthandcolonyformation.InIL‐3‐dependentleukemicTF‐1.8cells,weobservedincreasedβ‐cateninproteinlevelsandnuclearlocalizationinresponsetoIL‐3,andthiscorrelatedwithtranscriptionalinductionofβ‐catenintargetgenes.Furthermore,IL‐3promotedβ‐cateninaccumulationinasubsetofAMLpatientsamples,andgene‐expressionprofilingofthesecellsrevealedinductionofWNT/β‐cateninandTCF4genesignaturesinanIL‐3‐dependentmanner.Thisstudyisthefirsttolinkβ‐cateninactivationtoIL‐3andsuggeststhattargetingIL‐3signalingmaybeaneffectiveapproachfortheinhibitionofβ‐cateninactivityinsomepatientswithAML...

【 授权许可】

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