Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia

Margherita Ghisi, Lev Kats, Frederick Masson, Jason Li, Tobias Kratina, Eva Vidacs, Omer Gilan, Maria A. Doyle, Andrea Newbold, Jessica E. Bolden, Kirsten A. Fairfax, Carolyn A. de Graaf, Matthew Firth, Johannes Zuber, Ross A. Dickins, Lynn M. Corcoran, Mark A. Dawson, Gabrielle T. Belz, Ricky W. Johnstone

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11 Citations (Scopus)

Abstract

E proteins and their antagonists, the Id proteins, are transcriptional regulators important for normal hematopoiesis. We found that Id2 acts as a key regulator of leukemia stem cell (LSC) potential in MLL-rearranged acute myeloid leukemia (AML). Low endogenous Id2 expression is associated with LSC enrichment while Id2 overexpression impairs MLL-AF9-leukemia initiation and growth. Importantly, MLL-AF9 itself controls the E-protein pathway by suppressing Id2 while directly activating E2-2 expression, and E2-2 depletion phenocopies Id2 overexpression in MLL-AF9-AML cells. Remarkably, Id2 tumor-suppressive function is conserved in t(8;21) AML. Low expression of Id2 and its associated gene signature are associated with poor prognosis in MLL-rearranged and t(8;21) AML patients, identifying the Id2/E-protein axis as a promising new therapeutic target in AML.

Original languageEnglish
Pages (from-to)59-74
Number of pages16
JournalCancer Cell
Volume30
Issue number1
DOIs
Publication statusPublished - 11 Jul 2016

Cite this

Ghisi, M., Kats, L., Masson, F., Li, J., Kratina, T., Vidacs, E., Gilan, O., Doyle, M. A., Newbold, A., Bolden, J. E., Fairfax, K. A., de Graaf, C. A., Firth, M., Zuber, J., Dickins, R. A., Corcoran, L. M., Dawson, M. A., Belz, G. T., & Johnstone, R. W. (2016). Id2 and E proteins orchestrate the initiation and maintenance of MLL-rearranged acute myeloid leukemia. Cancer Cell, 30(1), 59-74. https://doi.org/10.1016/j.ccell.2016.05.019