Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression Journal Article
| Authors: | Wang, L.; Man, N.; Sun, X. J.; Tan, Y.; Cao, M. G.; Liu, F.; Hatlen, M.; Xu, H.; Huang, G.; Mattlin, M.; Mehta, A.; Rampersaud, E.; Benezra, R.; Nimer, S. D. |
| Article Title: | Regulation of AKT signaling by Id1 controls t(8;21) leukemia initiation and progression |
| Abstract: | Transcriptional regulators are recurrently altered through translocations, deletions, or aberrant expression in acute myeloid leukemia (AML). Although critically important in leukemogenesis, the underlying pathogenetic mechanisms they trigger remain largely unknown. Here, we identified that Id1 (inhibitor of DNA binding 1) plays a pivotal role in acute myeloid leukemogenesis. Using genetically modified mice, we found that loss of Id1 inhibited t(8;21) leukemia initiation and progression in vivo by abrogating protein kinase B (AKT)1 activation, and that Id1 interacted with AKT1 through its C terminus. An Id1 inhibitor impaired the in vitro growth of AML cells and, when combined with an AKT inhibitor, triggered even greater apoptosis and growth inhibition, whereas normal hematopoietic stem/progenitor cells were largely spared. We then performed in vivo experiments and found that the Id1 inhibitor significantly prolonged the survival of t(8;21)1 leukemic mice, whereas overexpression of activated AKT1 promoted leukemogenesis. Thus, our results establish Id1/Akt1 signaling as a potential therapeutic target in t(8;21) leukemia. © 2015 by The American Society of Hematology. |
| Keywords: | signal transduction; protein kinase b; cancer survival; controlled study; cancer growth; nonhuman; animal cell; mouse; apoptosis; inhibitor of differentiation 1; carboxy terminal sequence; protein depletion; protein protein interaction; animal experiment; animal model; in vivo study; in vitro study; cancer inhibition; leukemia cell; leukemogenesis; acute myeloblastic leukemia; tamoxifen; fetus; hematopoietic stem cell; protein kinase b inhibitor; priority journal; article; cannabidiol |
| Journal Title: | Blood |
| Volume: | 126 |
| Issue: | 5 |
| ISSN: | 0006-4971 |
| Publisher: | American Society of Hematology |
| Date Published: | 2015-07-30 |
| Start Page: | 640 |
| End Page: | 650 |
| Language: | English |
| DOI: | 10.1182/blood-2015-03-635532 |
| PROVIDER: | scopus |
| PMCID: | PMC4520879 |
| PUBMED: | 26084673 |
| DOI/URL: | |
| Notes: | Export Date: 2 October 2015 -- Source: Scopus |
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