# Oncogenic Roles and Therapeutic Potential of MCL1 Addiction in Primary Effusion Lymphoma

> **NIH NIH K22** · UNIV OF ARKANSAS FOR MED SCIS · 2022 · $158,397

## Abstract

Project Summary
Primary effusion lymphoma (PEL) is an aggressive B cell lymphoma caused by the DNA tumor virus Kaposi’s
sarcoma-associated herpesvirus (KSHV). PEL is an unusual cancer in that no recurrent mutations have been
reported in tumors. Instead, PEL requires the continued expression of virally encoded oncogenes to alter the
cellular transcriptome in latently infected cells. Candidate approaches have left us with a limited view of what
cellular oncogenes are required by the viral lymphoma. It is not surprising that no effective and specific therapy
is available to treat this disease. We have recently identified 210 human genes, called PEL-specific oncogenic
dependencies (PSODs), that are critically important for the survival of these tumor-derived cell lines using
genome-wide CRISPR/Cas9 screens. We have shown that PEL cell lines exhibit a specialized requirement for
the anti-apoptotic protein MCL1 despite having high levels of other related BCL2 proteins. New functions of
MCL1 have started to emerge independent of its canonical role in preventing apoptosis. It is not clear whether
this selective requirement for MCL1 over the other BCL2 proteins is due to a need to block a specific apoptotic
stress or whether MCL1 plays a non-canonical function in PEL. Nevertheless we have shown that we can
leverage this dependency by pharmacologically inhibiting MCL1 using the small molecule compound S63845.
In Aim 1, I will test the therapeutic potential of S63845 for treating PEL in a xenograft mouse model. In Aim 2, I
will investigate why PEL is addicted to MCL1. Specifically in Aim 2A, I will study the role of MCL1 in blocking
the activities of the p53 tumor suppressor family. In Aim 2B, I will take an unbiased approach and perform
CRISPR screens to identify genetic interactions of MCL1. Together, I expect that this study will uncover new
insights into the biology of MCL1 in general, answer why MCL1 is important in PEL, and develop MCL1 as a
new therapeutic target for this cancer. Completion of this award will open new research areas for my career as
an independent investigator in viral lymphomas.

## Key facts

- **NIH application ID:** 10469489
- **Project number:** 5K22CA241355-03
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Mark Manzano
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $158,397
- **Award type:** 5
- **Project period:** 2020-09-04 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10469489

## Citation

> US National Institutes of Health, RePORTER application 10469489, Oncogenic Roles and Therapeutic Potential of MCL1 Addiction in Primary Effusion Lymphoma (5K22CA241355-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10469489. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*