Highlights of FOXM1 Research

Published in Nature Communication on Feb. 17, 2020

Relapse is the major cause of death after acute myeloid leukemia (AML) treatment.  Leukemia stem cells (LSCs) are a small population of leukemia cells that possess the capacity of enhanced self-renewal and leukemia initiation, and are able to differentiate to bulk leukemia cells. Most LSCs are in a quiescent state, and often evade cytotoxic effects of anticancer drugs, which target rapidly proliferating cells. Therefore, the development of new therapeutic approaches targeting LSCs may be more effective for eradicating leukemia. Our group has identified a vital gene FOXM1 which plays an important function in LSCs—-targeting FOXM1 can specifically eliminate LSCs in MLL-rearranged AML. The results are published in the journal Nature Communications recently.

The research focused on a subtype of AML—MLL rearranged (MLL-r) AML. MLL-r AML has a poor diagnostic, drug-resistant, and high recurrence. We found that FOXM1 is specific highly expressed in MLL-r AML, indicating hat FOXM1 plays an oncogenic role in this subtype of AML. To investigate the functions of FOXM1, the researchers have established murine leukemia models with presence and absence of FOXM1. Compared to the control group, leukemia cells with deletion of Foxm1 grew much slower in vitro and in vivo. Flow cytometric analysis showed that Foxm1-deficient LSCs were less quiescent and underwent a significantly higher apoptosis rate, which leads to loss of the cell number and impaired cell functions of LSCs.

Next, FOXM1 inhibitors-Siomycin A, Thiostrepton and specific target peptide were introduced to treat the AML cells in vitro and in vivo. We found that FOXM1 inhibition significantly suppressed MLL-r AML cells growth and induced undergoing apoptosis while it had a less effect on non-MLL-r AML cells and had a minimal effect on normal healthy cord blood CD34+ cells. Patient-derived Xenograft mouse models showed that FOXM1 inhibition resulted in a reduction of quiescence and elevating apoptosis of LSCs, which lead to a less leukemia burden and a longer survival rate. More importantly, we demonstrated a novel molecular mechanism underlying the role of Foxm1 in LSCs by stabilizing b-catenin, a critical oncogenic protein, through directly interacting with b-catenin.

It is an exciting finding, because targeting LSCs may benefit MLL-r patients, especially the patients undergoing drug resistance and relapse.  To elucidate the role of Foxm1 in chemoresistance, we treated the MLL-AF9 induced leukemia mice with the presence or absence of Foxm1 with the first line standard chemotherapy regimen (Ara-C and Doxorubicin) in humans.  Chemotherapy drugs only slightly delayed the AML onset in leukemia mice with presence of Foxm1, but they significantly reduced AML burden and prolonged the survival of the leukemia mice with absence of Foxm1.

Next we will apply our finding from bench-to-bed, more specific FOXM1 inhibitors generation are in process and the clinical trial is on the way. The study’s first author is Dr. Yue Sheng, who is a research assistant professor in Cancer Center. Other collaborators include Chunjie Yu, Yin Liu, Cao hu, and Rui Ma. Dr. Jonathan D. Licht has provided critical advices and helps on this project.

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