# Targeting blastic plasmacytoid dendritic cell neoplasm (BPDCN)

> **NIH NIH R37** · DANA-FARBER CANCER INST · 2020 · $444,222

## Abstract

Project Summary
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 t...

## Key facts

- **NIH application ID:** 9857572
- **Project number:** 5R37CA225191-03
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Andrew A Lane
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $444,222
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9857572

## Citation

> US National Institutes of Health, RePORTER application 9857572, Targeting blastic plasmacytoid dendritic cell neoplasm (BPDCN) (5R37CA225191-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9857572. Licensed CC0.

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