Epigenetic basis of lineage plasticity and therapy resistance of T-lineage-derived myeloid leukemia stem cells

Basic data for this project

Description

Lineage plasticity in cancer can cause therapy resistance and poor patient survival. Therefore, understanding how lineage plasticity originates is important for the development of new clinical therapies. Acute leukemia is a particularly suitable disease for studying lineage plasticity because in up to 20% of cases, cells either express markers of several lineages or can switch lineage identity. Although the underlying cellular origin remains poorly defined, it is generally assumed that these cases arise from malignant transformation of multi-potent hematopoietic stem cells. However, we could recently demonstrate an alternative mechanism in which plasticity in leukemia can result from instable lineage identity inherited from differentiating progenitor cells. Using a Myc-driven mouse model in combination with single cell assays, we found that CD4-/CD8- double negative 2 (DN2) T-cell progenitors possess significant potential to convert lineage and transform into myeloid and biphenotypic leukemia. Remarkably, these transdifferentiated cancer cells retained expression of a defined set of T-cell transcription factors, forming an epigenetic memory which propagates growth and myeloid/T-lymphoid instability. Based on these characteristics, we identified a correlating human leukemia cohort and, revealed targeting of Jak2/Stat3-signaling by ruxolitinib as a therapeutic possibility. Consequently, our study suggests early T-cell progenitors as a source of a unique kind of AML. Building on these findings, in this proposal our goals are now to use our mouse model to isolate the leukemia-driving ‘stem' cells and uncover the underlying molecular disease mechanisms of this DN2-related AML, as well as to develop a diagnostic marker panel, evaluate therapeutic options and conduct a comprehensive clinical characterization of the correlating human disease. We believe that our results will contribute to the mechanistic understanding of lineage plasticity as a driving mechanism of cancer. Importantly, because we could find that DN2-related AML has unique phenotypic and molecular features distinguishing it from other AMLs, we believe that our results will lead to improved treatment options for this AML type by blocking pathways specific (such as JAK2) and thus will benefit the respective patients.