Disordered epigenetic regulation of the CREBBP oncoprotein and of micro-RNA transcription in juvenile myelomonocytic leukemia at high risk of relapse

• Applicant: Professor Dr. Christian Flotho
• Subject Area: Hematology, Oncology
• Term: from 2010 to 2018
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 171803176

Our previous work indicates that juvenile myelomonocytic leukemia (JMML), an aggressive myeloproliferative neoplasm of early childhood, is a disease with impaired DNA methylation control. A subset of patients carry a leukemic clone with extensive DNA hypermethylation at specific target sites. These children face a serious risk of disease recurrence after transplantation. Using genome-wide CpG methylation profiling in a pilot series of JMML cases, we identified the cAMP-responsive element binding protein (CREB)-binding protein CREBBP, a transcriptional co-activator and histone acetyltransferase with a well-documented role in myeloid leukemogenesis, as a target of epigenetic modification in high-risk JMML. In addition, several loci encoding micro-RNAs were altered by DNA hypermethylation. Here we propose to investigate how epigenetic dysregulation 1) of CREBBP, and 2) of specific micro-RNAs, contributes functionally to the refractory JMML phenotype.First, we will perform a systematic screen for epigenetic CREBBP modification in an extended cohort of JMML patients, corroborate the adverse prognostic significance of such lesions, use reporter constructs to analyze the effects of CREBBP CpG island methylation on its expression in detail, study the expression patterns of CREBBP in low-risk versus high-risk JMML, look into the phenotypic consequences of experimental CREBBP repression in JMML, and define target promoters whose function is impaired when CREBBP becomes dysfunctional in JMML.Second, we will study the genome-wide spectrum of micro-RNAs with epigenetic promoter modification in JMML, identify target structures of aberrantly regulated micro-RNAs in JMML, and characterize the functional role of epigenetic micro-RNA silencing in this leukemia.We anticipate that these investigations will enhance our understanding of the close link between epigenetic aberrations and aggressive phenotype in JMML, that they will provide valuable insight into the role of epigenetic dysregulation in the initiation of myeloid leukemia, and that they will provide functional explanation for the high rate of failure after HSCT for JMML. Moreover, these studies will strengthen the preclinical rationale for the use of epigenetic therapy in JMML.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1463: Epigenetic Regulation of Normal Hematopoiesis and its Dysregulation in Myeloid Neoplasia
• Participating Person: Professorin Dr. Charlotte Niemeyer