The Wang Lan research group of the Institute of Nutrition and Health collaborated to reveal a new mechanism by which UHRF1 regulates acute myeloid leukemia

On October 27, 2022, the international academic journal Cell Research published online the latest research results
entitled "Targeting UHRF1-SAP30-MXD4 axis for leukemia initiating cell eradication in myeloid leukemia", published online by Wang Lan's research group at the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences 。 This study elucidated the mechanism of action of UHRF1 in the development and maintenance of acute myeloid leukemia (AML) and screened specific small molecule inhibitors against UHRF1, which provided a theoretical basis and potential diagnosis and treatment strategies
for the clinical treatment of AML.

AML is a clonal disease with abnormal hematopoietic stem/progenitor cells characterized by an increase in
immature myeloid cells in the bone marrow.
AML is the most common acute leukemia in adults, with a 5-year overall survival rate of 25-40%
for patients with AML.
The prognosis is worse for older patients who are not candidates for intensive chemotherapy and for patients with relapsed or refractory AML
.
Although chemotherapy is still the mainstay of treatment for many AML patients, conventional chemotherapy in AML patients often does not effectively target AML-initiating cells
.
Therefore, there is an urgent need for new therapeutic strategies to target the self-renewal
of AML-initiating cells.

In this study, the researchers found that UHRF1 was significantly high expressed in cells of AML patients, and the high expression of UHRF1 was significantly associated
with poor prognosis in AML patients.
Using a Uhrf1 conditional knockout mouse model, the researchers found that Uhrf1 deletion significantly delayed the onset, maintenance and development of AML and significantly inhibited the self-renewal
of AML-initiating cells.
Mechanically, through RNA-seq data analysis in different types of AML cells, the researchers found that knocking down UHRF1 can significantly enrich signaling pathways such as MYC, E2F and G2/M
.
Combined with CUT&Tag and DNA methylation analysis, UHRF1 promoted the expression
of MXD4 by reducing the DNA methylation level of the target MXD4.
As an antagonist of MYC, the high expression of MXD4 can significantly inhibit the downstream signaling pathway
of MYC.
The researchers found that knocking down Uhrf1 and Mxd4 simultaneously in mouse AML cells significantly restored the decrease in leukemia initiation cells and prolonged
survival in AML mice caused by Uhrf1 knockdown.
To further investigate how UHRF1 regulates the expression of the target gene MXD4, the researchers found that UHRF1 interacts with SAP30 through mass spectrometry and confirmed that G572 and F573 sites located on the UHRF1-SRA domain can directly interact
with SAP30.
When these sites were mutated in UHRF1-knocked down AML cells, it led to a decrease in DNA methylation levels and increased expression of the target gene MXD4, while significantly delaying AML survival in
mice.
The researchers also found that in AML cells, SAP30 co-regulates the binding of the target gene MXD4 by interacting with UHRF1, thereby affecting its expression and proliferation of AML cells
.

In order to study the targeted therapeutic effect of UHRF1 in AML, the researchers used molecular simulation combined with deep learning to screen for UF146, a small molecule inhibitor that can specifically inhibit the binding of UHRF1-SRA domain to semimethylated DNA, and found that UF146 can significantly inhibit the proliferation and self-renewal ability of
mouse AML initiator cells and primary cells in AML patients.
The researchers found that UF146 can promote the expression level
of the target gene MXD4 by inhibiting its DNA methylation.
Finally, the researchers found that the survival of AML in UF146-treated mice was significantly delayed, and PDX experiments showed that UF146 had a significant therapeutic effect
on xenograft models derived from AML patients.
In summary, this study reveals that UHRF1 regulates the occurrence and development of AML through AML-initiated cells, and the study of small molecule inhibitors targeting UHRF1 may have important guiding significance
for the treatment of clinical AML.

Researcher Wang Lan of Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Zheng Mingyue, researcher of Shanghai Institute of Materia Medica, Chinese Academy of Sciences, researcher Sun Xiaojian, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, and researcher Liu Xiaolong, Center for Excellence in Molecular and Cell Science, Chinese Academy of Sciences, are the corresponding authors of the paper, postdoctoral fellow Hu Chenglong, postdoctoral fellow Chen Bingyi, doctoral student Li Zijuan, Yang Tianbiao, a doctoral student at the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and Xu Chunhui, a doctoral graduate from the Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, are the first authors
of the paper.
This work has been strongly supported by a number of medical and scientific research collaborators, including Academician Chen Saijuan and Chen Zhu from Ruijin Hospital affiliated to Shanghai Jiao Tong University School of Medicine, Chief Physician Shen Shuhong of Shanghai Children's Medical Center affiliated to Shanghai Jiao Tong University School of Medicine, Chief Physician Chang Chunkang and Chief Physician Wu Lingyun of Shanghai Sixth People's Hospital affiliated to Shanghai Jiao Tong University School of Medicine, and Chief Physician Zhang Qunling of Fudan University Cancer Hospital
.
This project was supported
by the National Natural Science Foundation of China, the Ministry of Science and Technology, the Chinese Academy of Sciences, and the State Key Laboratory of Medical Genomics.

Schematic diagram
of the molecular mechanism by which UHRF1 regulates AML.