| First Author | Nayak RC | Year | 2019 |
| Journal | Nat Commun | Volume | 10 |
| Issue | 1 | Pages | 46 |
| PubMed ID | 30610188 | Mgi Jnum | J:270586 |
| Mgi Id | MGI:6277463 | Doi | 10.1038/s41467-018-07846-y |
| Citation | Nayak RC, et al. (2019) The signaling axis atypical protein kinase C lambda/iota-Satb2 mediates leukemic transformation of B-cell progenitors. Nat Commun 10(1):46 |
| abstractText | Epigenetically regulated transcriptional plasticity has been proposed as a mechanism of differentiation arrest and resistance to therapy. BCR-ABL leukemias result from leukemic stem cell/progenitor transformation and represent an opportunity to identify epigenetic progress contributing to lineage leukemogenesis. Primary human and murine BCR-ABL(+) leukemic progenitors have increased activation of Cdc42 and the downstream atypical protein kinase C (aPKC). While the isoform aPKCzeta behaves as a leukemic suppressor, aPKClambda/iota is critically required for oncogenic progenitor proliferation, survival, and B-cell differentiation arrest, but not for normal B-cell lineage differentiation. In vitro and in vivo B-cell transformation by BCR-ABL requires the downregulation of key genes in the B-cell differentiation program through an aPKC lambda/iota-Erk dependent Etv5/Satb2 chromatin repressive signaling complex. Genetic or pharmacological targeting of aPKC impairs human oncogenic addicted leukemias. Therefore, the aPKClambda/iota-SATB2 signaling cascade is required for leukemic BCR-ABL(+) B-cell progenitor transformation and is amenable to non-tyrosine kinase inhibition. |
