Posted December 14, 2017

Sihem Cheloufi, Ph.D., University of California, Riverside

Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, accounting for up to 30% of newly-diagnosed leukemia cases each year. AML is marked by a blockage in the hematopoietic cascade, the tightly regulated sequence by which stem cells differentiate into mature blood cell types. An imbalance in the differentiation of the myeloid type of progenitors in AML results in their uncontrolled growth. Treatments for AML include chemical and radiation therapy, which have severe side effects for patients. As a result, there is an urgent need for targeted therapies that do not have these negative effects. With support from a Fiscal Year 2012 (FY12) Visionary Postdoctoral Fellowship Award, Dr. Sihem Cheloufi proposed to study specific molecules that alter gene expression in AML.

The initial goal of Dr. Cheloufi's work was to exploit common pathways used by both cellular reprogramming and carcinogenic processes. Carcinogenesis may have pathways in common with cellular reprogramming, a methodology whereby mature or differentiated cells are reprogrammed to their immature or de-differentiated state. In this methodology, de-differentiated cells acquire stem cell characteristics and become induced pluripotent stem cells (iPSCs). Current research into AML is focused on identifying molecules involved in chromatin regulation (the way DNA is associated with RNA and proteins) that push cells to deviate from the well-controlled hematopoietic system and proliferate out of control, leading to cancer. During the award period, Dr. Cheloufi identified critical chromatin regulators that could have broad implications for cancer therapy. Chromatin regulators are factors that affect whether genes are on or off. Normally, DNA is tightly coiled around proteins, called histones, that participate in the regulation of its activity. To identify the important chromatin regulators, Dr. Cheloufi used RNAi screens, a methodology in which RNA molecules are used to interfere with gene expression. Through these comprehensive RNAi screens, chromatin assembly factor (CAF)-1 histone chaperon complex was determined to be a major roadblock during the reprogramming of cells into iPSCs. Due to the parallel nature of cellular reprogramming and carcinogenesis, Dr. Cheloufi explored the role of CAF-1 and observed that inhibition of CAF-1 resulted in improved chromatin accessibility, which in turn increased cellular reprogramming efficiency. Dr. Cheloufi further demonstrated that the effect of CAF-1 inhibition can be more generic. For example suppression of CAF-1 enhances direct conversion of pre-B lymphocytes into mature macrophages and that of fibroblasts into neurons. Given the key role of CAF-1 in cellular reprogramming, Dr. Cheloufi asked whether the same mechanism contributed to carcinogenesis, in which case the modulation of chromatic assembly molecules, such as CAF-1, could be used to facilitate reprogramming cells to model disease states and direct novel therapeutic strategies. Dr. Cheloufi is investigating the outcomes of manipulating CAF-1 in leukemia cells. Her data suggest that inhibition of CAF-1 alone relieves the differentiation block of pre-leukemic cells.

Dr. Cheloufi's work highlights the importance of pinpointing the specific molecules involved in chromatin regulation to generate therapeutically relevant cell types and design novel strategies to eliminate cancerous cells. This work also implies that molecules involved in fundamental processes, such as chromatin assembly, may serve as potential stabilizers for maintaining cell identity.

During her postdoctoral fellowship at the Massachusetts General Hospital, she received follow-on funding from Harvard Medical School to investigate the effect of CAF-1 suppression-induced reprogramming on histone variants. Dr. Cheloufi was able to receive this grant to continue her research with CAF-1 due to the groundwork completed through her Visionary Postdoctoral Fellowship Award. As a result of her successful findings, Dr. Cheloufi was appointed to an independent faculty position at the Biochemistry Department at the University of California, Riverside. Dr. Cheloufi hopes that her work will ultimately lead to new treatment strategies for AML and possibly other types of cancers. A patent application has been filed for the discovery of CAF-1 as a regulator of cell reprogramming and differentiation.

References:

Cheloufi S, Hochedlinger K. Emerging roles of the histone chaperone CAF-1 in cellular plasticity. (2017) Current Opinion in Genetics and Development, 46:83-94

Borkent M, Bennett BD, Lackford B, et al. 2016. Serial shRNA screen for roadblocks to reprogramming identifies the protein modifier SUMO2. Stem Cell Reports 6(5):704-716.

Cheloufi S, Elling U, Hopfgartner B, et al. 2015. The histone chaperone CAF-1 safeguards somatic cell identity. Nature 528(7581):218-224.

Link:

Public and Technical Abstracts: Investigating Epigenetic Parallels between Carcinogenesis and Reprogramming to Pluripotency

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