Transcription factor RUNX1 promotes survival of acute myeloid leukemia cells
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
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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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 8

Critical role of RUNX1/CBFB complex in murine MLL fusion leukemia.

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Critical role of RUNX1/CBFB complex in murine MLL fusion leukemia. (A) E...
(A) Experimental scheme used in B–D. Murine bone marrow progenitors derived from wild-type, Runx1/Cbfbf/wt, Cbfbf/f, and two independent Runx1/Cbfbf/f mice were transduced with MLL-AF9. Immortalized cells from the third to fifth rounds of in vitro plating were subsequently transduced with a Cre-YFP–expressing retrovirus. Both YFP– (nontransduced) and YFP+ (Cre-transduced) cells were sorted, and then their clonogenic activity and surface marker expression were assessed in the further rounds of plating. (B) Numbers of colonies generated by Cre-transduced (YFP+) or nontransduced (YFP–) MLLAF9 cells bearing floxed alleles for Runx1, Cbfb, or both. Data are shown as the mean ± SD from duplicate plates. (C) Wright Giemsa staining of Runx1/Cbfb-deleted (YFP+) and nondeleted (YFP–) MLL-AF9 cells. Original magnification, ×40. (D) GR-1 and c-KIT expression in the indicated MLL-AF9 cells with or without Cre-YFP expression. The percentage of GR-1+/c-KIT+ cells is indicated. Loss of RUNX1/CBFB resulted in a significant reduction of GR-1+/c-KIT+ cells. Loss of CBFB also reduced GR-1 expression. (E) Survival curves of the mice transplanted with MLL-AF9 leukemia cells bearing MxCre and homozygous Runx1/Cbfb floxed alleles. Data from 8 (PBS) and 6 (pIpC) mice are shown. P = 0.005, log-rank test. (F) PCR genotyping of GFP+ MLL-AF9 cells on day 15 (immediately after pIpC injection) and on day 30 from moribund mice. Excision of Runx1 was observed on day 15, but leukemia cells on day 30 primarily harbored a nonexcised Runx1 allele.