# Regulation of Bcl-2 dependence in multiple myeloma

> **NIH NIH K08** · EMORY UNIVERSITY · 2023 · $242,898

## Abstract

PROJECT SUMMARY/ABSTRACT
Multiple myeloma is an incurable malignancy of plasma cells for which new treatments and precision guided
approaches are acutely needed. Current treatments target the plasma cell biology thought to be common to all
myeloma. However, response to these treatments is highly variable pointing to an underlying heterogeneity in
biology. One recently identified source of heterogeneity with important therapeutic implications involves
dependence on the Bcl-2 family of proteins, which includes Bcl-2, Bcl-xL, and Mcl-1. These proteins regulate cell
survival and are the targets of a new class of drugs being studied for use in myeloma. Although both normal
plasma cells and myeloma are typically dependent on Mcl-1 for survival, a subset of myeloma with a B cell-like
phenotype is Bcl-2 dependent and sensitive to venetoclax, a Bcl-2 specific inhibitor. This B cell phenotype is
notable because B cells are also Bcl-2 dependent and B cell malignancies such as CLL are highly sensitive to
venetoclax. The objective of this proposal is to test the hypothesis that in a subset of myeloma, B cell
transcriptional and signaling networks remain active and contribute to Bcl-2 dependence and venetoclax
sensitivity as well as resistance to conventional plasma cell directed therapy. The studies proposed will define
the mechanisms of Bcl-2 family dependence in myeloma and identify biomarkers capable of selecting myeloma
patients most likely to respond to Bcl-2 inhibitors such as venetoclax. Aim 1 will characterize the mechanisms of
BATF3 activity, an AP-1 transcription factor that increases Bcl-2 dependence and sensitizes myeloma to
venetoclax, using genomic and epigenomic analyses on cells with CRISPR mediated BATF3 overexpression or
knockdown. Aim 2 will directly interrogate the origins of Bcl-2 dependence and intrinsic resistance to venetoclax
in myeloma using CRISPR screens targeting genes that are differentially expressed in venetoclax sensitive and
resistant cells. Finally, Aim 3 will utilize state of the art mass cytometry on ex vivo tested myeloma patient
samples to develop a novel biomarker that could be used for future precision medicine trials to predict response
to inhibitors of Bcl-2, Bcl-xL, and Mcl-1. These studies will be conducted by Dr. Vikas Gupta, whose long-term
career goal is to become an independently funded physician-scientist studying the molecular pathogenesis of
multiple myeloma. He is seeking an NIH K08 career development award to acquire the additional skills necessary
for independence. With the help of a multi-disciplinary group of experts serving as mentors and advisors, he will
receive hands on training in advanced research techniques such as targeted CRISPR screens, RNA sequencing,
bioinformatics, and mass cytometry as well as mentoring in manuscript and grant writing, clinical trial
development, laboratory management, and leadership skills. Completion of the work proposed here will lay the
foundation for future R01 applic...

## Key facts

- **NIH application ID:** 10691502
- **Project number:** 5K08CA267055-02
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Vikas Anand Gupta
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $242,898
- **Award type:** 5
- **Project period:** 2022-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10691502

## Citation

> US National Institutes of Health, RePORTER application 10691502, Regulation of Bcl-2 dependence in multiple myeloma (5K08CA267055-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10691502. Licensed CC0.

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