Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
Susumu Goyama, … , Gang Huang, James C. Mulloy
Susumu Goyama, … , Gang Huang, James C. Mulloy
Published August 27, 2013
Citation Information: J Clin Invest. 2013;123(9):3876-3888. https://doi.org/10.1172/JCI68557.
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Research Article Oncology

Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells

Abstract

RUNX1 is generally considered a tumor suppressor in myeloid neoplasms. Inactivating RUNX1 mutations have frequently been found in patients with myelodysplastic syndrome (MDS) and cytogenetically normal acute myeloid leukemia (AML). However, no somatic RUNX1 alteration was found in AMLs with leukemogenic fusion proteins, such as core-binding factor (CBF) leukemia and MLL fusion leukemia, raising the possibility that RUNX1 could actually promote the growth of these leukemia cells. Using normal human cord blood cells and those expressing leukemogenic fusion proteins, we discovered a dual role of RUNX1 in myeloid leukemogenesis. RUNX1 overexpression inhibited the growth of normal cord blood cells by inducing myeloid differentiation, whereas a certain level of RUNX1 activity was required for the growth of AML1-ETO and MLL-AF9 cells. Using a mouse genetic model, we also showed that the combined loss of Runx1/Cbfb inhibited leukemia development induced by MLL-AF9. RUNX2 could compensate for the loss of RUNX1. The survival effect of RUNX1 was mediated by BCL2 in MLL fusion leukemia. Our study unveiled an unexpected prosurvival role for RUNX1 in myeloid leukemogenesis. Inhibiting RUNX1 activity rather than enhancing it could be a promising therapeutic strategy for AMLs with leukemogenic fusion proteins.

Authors

Susumu Goyama, Janet Schibler, Lea Cunningham, Yue Zhang, Yalan Rao, Nahoko Nishimoto, Masahiro Nakagawa, Andre Olsson, Mark Wunderlich, Kevin A. Link, Benjamin Mizukawa, H. Leighton Grimes, Mineo Kurokawa, P. Paul Liu, Gang Huang, James C. Mulloy

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Figure 2

Mutant RUNX1 inhibits the growth of human AML cells by inducing cell cycle arrest and apoptosis.

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Mutant RUNX1 inhibits the growth of human AML cells by inducing cell cyc...
(A and B) Changes in frequency of GFP+ cells (vector/RUNX1/mutant-expressing cells) in two independent cultures of AML1-ETO (A) and MLL-AF9 cells (B). (C) CD34 and CSF2RA expression in vector/RUNX1/mutant-transduced AML1-ETO cells. The percentage of CD34+ cells in each culture is indicated. (D and E) Cells were transduced with vector, RUNX1, or its mutants (D171N and S291fs) and were cultured with cytokines. Cell cycle status and apoptosis were assessed on days 5 through 7 of culture. The frequency of S/G2/M phase cells in GFP+ cells (transduced cells) was first normalized to that in GFP– cells (nontransduced cells) and then was normalized to that of the vector control (D). For apoptosis, the frequency of annexin V+ cells in GFP+ cells was normalized to that of the vector control (E). Three or four independent experiments were performed, and data are shown as the mean ± SEM.