Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is an orphan hematologic malignancy that is clinically aggressive and fatal in most patients within one year of diagnosis. The disease pathogenesis is largely unknown, there is no standard treatment, and patients with BPDCN have a clear unmet medical need. The long-term goal is to improve outcomes in BPDCN by deeper understanding of disease biology. DNA sequencing in BPDCN revealed a high frequency of mutations in RNA splicing factors, with particular enrichment in loss-of-function mutations in ZRSR2 compared to other cancers. Functional assessment of patient tumors found that BPDCN is uniquely dependent on the anti-apoptotic protein BCL2 and is highly sensitive to treatment with the BH3 mimetic venetoclax. New genetically engineered models of dendritic cell leukemia and BPDCN patient-derived xenografts offer a unique opportunity to test the contribution of disease alleles to splicing abnormalities and therapeutic response. The overall objective of this application is to test the hypothesis that genetic alterations associated with BPDCN contribute to dendritic cell transformation and create targetable vulnerabilities. Guided by strong preliminary data from the applicant's laboratory and an established network of expert collaborators, this central hypothesis will be tested by pursuing two specific aims: 1) Determine how ZRSR2 mutation promotes dendritic cell transformation; and 2) Identify factors that generate unique apoptotic dependencies in BPDCN. Under the first Aim, the applicant will use genetic models of ZRSR2 deficiency in dendritic cells and BPDCNs to determine how splicing mutations alter the transcriptome and cause transformation of the dendritic lineage. They will also test how mutations in ZRSR2, a gene located on the X chromosome that escapes X-inactivation in female cells, contributes to the male bias of BPDCN and sensitizes to splicing modulator therapy. Under the second Aim, the mechanisms of BCL2 dependence in normal and malignant dendritic cells will be investigated in human and mouse hematopoiesis. Adaptations to chemotherapy in BPDCN will be measured to determine if BCL2 inhibition can overcome chemoresistance, which is the major barrier to improved outcomes in patients. The approach is innovative by making use of novel model systems and samples from BPDCN patients on active clinical trials. The downstream effects of ZRSR2 mutations on BPDCN and male cancer predominance have not been clarified, and the mechanisms of protection from apoptosis in normal and malignant dendritic cells are unknown. The proposed research is significant, because it is expected to define the biological role of clinically-relevant mutations in an understudied and highly fatal disease. The expected output for the proposed research is that the knowledge gained will be immediately clinically significant for patients with BPDCN because it will inform new treatment strategies in a cancer that is currently lacking in significant biological and therapeutic insight.
The proposed research is relevant to public health because BPDCN is a highly fatal yet understudied malignancy, in which there is no standard therapy and the mechanisms of dendritic cell transformation are not known. This project is relevant to the NIH's mission to gain fundamental knowledge to reduce illness because it will elucidate treatment strategies in BPDCN based on understanding of the genetic basis of the disease.