New Insights into Molecular Determinants of Leukemia Development and Maintenance

Acute myeloid leukemia (AML) is an aggressive blood cancer that affects mainly adults and its occurrence increases with age. Despite some treatment improvements, many patients face poor outcomes due to the complex nature of the disease and frequent relapses. To develop better treatments, a deeper understanding of the molecular causes of AML is crucial.

In this January, a new research group was established at the Robert Bosch Center for Tumor Diseases (RBCT) on the Bosch Health Campus, led by Dr. Haiyang Yun, a scientist with extensive research training in experimental hematology from Hannover, Cambridge (UK) and Heidelberg. Dr. Yun’s group focuses on investigating gene regulatory mechanisms in blood cancers, aiming to advance our understanding and treatment of these diseases. In close collaboration with external researchers, Dr. Yun has recently made new discoveries of molecular factors that drive AML. These findings from two separate studies are published in the journal Leukemia.

In the first study, Dr. Yun worked with Prof. Carsten Müller-Tidow and colleagues at University Hospital Heidelberg to investigate chromatin-associated small non-coding RNAs (ncRNAs) in leukemia cells. Unlike the RNAs that make proteins, ncRNAs regulate various genetic processes and have been relatively unexplored in leukemia.

Using a cutting-edge technique called iMARGI, the team mapped the interaction landscape between RNA and chromatin in AML cells. They discovered two specific small ncRNAs (Figure 1), namely SNORD118 and SNORD3A, predominantly interacted with chromatin in a trans manner (meaning inter-chromosomal associations), indicating prominent roles in chromatin modulation. These ncRNAs were actively transcribed in leukemia cells and increased during leukemia transformation, but decreased during normal myeloid cell differentiation. Suppressing SNORD118 and SNORD3A in leukemia cells significantly impaired their growth and reduced their ability to form colonies, while having minimal impact on healthy blood stem and progenitor cells. This indicates that targeting these ncRNAs could be a promising strategy for treating AML without harming normal cells.

In the second study, Dr. Yun collaborated with Prof. Zhixiong Li and his team at Hannover Medical School to explore how Cre recombinase affects leukemia development in a specific mouse model. This model carries the knock-in of FLT3 gene with internal tandem duplications (ITD), one of the most common mutations in AML, occurring in one out of three patients and associating with poor prognosis. Cre recombinase is a common tool for introducing genetic alterations in a controllable setting in transgenic mice.

Dr. Yun and collaborators found unexpectedly that Cre recombinase alone could trigger leukemia in mice with both homozygous and heterozygous FLT3-ITD mutation. Moreover, this pathogenesis involved the activation of an unknown regulatory element of FLT3 gene induced by Cre-mediated recombination. This work hinted the need for careful study design and data interpretation when using Cre-loxP recombination system in the context of FLT3-ITD knock-in mice for leukemia research.

These research unravels the complexities of the molecular pathogenesis of AML, offering potential new targets for AML intervention. As we continue to explore the genetic and molecular landscape of leukemia, we move closer to innovative treatments that could significantly improve outcomes for patients with this challenging disease. This research was supported by the research grants from Deutsche Forschungsgemeinschaft (DFG), Deutsche Krebshilfe, Deutsche José-Carreras-Leukämie-Stiftung and Robert Bosch Stiftung.