# Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma

> **NIH CA R01** · OHIO STATE UNIVERSITY · 2026 · $570,593

## Abstract

Project Summary
Double (DH) and triple-hit (TH) lymphomas (L) are rare high grade B-cell lymphomas with diffuse large B-cell
(DLBCL) morphology characterized by the co-occurrence of chromosomal translocations involving MYC,
BCL2, and/or BCL6. DLBCLs with dual c-Myc (>40% by immunohistochemistry, IHC) and BCL2 (>50% by IHC)
protein overexpression without translocation (double-expressor or DEL) are significantly more common than
DH/THL, accounting for 20% to 30% of DLBCL patients. Lymphoma with either DEL, DHL, or THL are here
collectively called c-Myc overexpressing LBCL and have a significantly worse prognosis compared to the c-
Myc-negative counterpart [3-year overall survival of ~30% versus 70%, respectively]. The poor clinical
outcome of this subset of lymphoma patients highlights the need for novel therapeutic strategies. Transducin
β-like protein 1 (TBL1X) was initially identified as a specific adaptor protein playing an essential role in
canonical Wnt signaling by recruiting β-catenin to the promoter region of Wnt targets such as MYC and
CCND1 to activate their transcription. Few published reports indicate that the Wnt/β-catenin signaling is
constitutively activated in DLBCL, which prompted our initial investigation in this disease. Preliminary data: Our
published work shows that, unlike normal B cells, DLBCL cells express abundant levels of TBL1. Genetic
deletion of TBL1 or pharmacologic treatment with tegavivint (Iterion), a first-in-class small molecule targeting
TBL1, induces significant DLBCL cell death in vitro and in vivo. While tegavivint was initially developed as an
inhibitor of the TBL1/β-catenin interaction, our data show that genetic deletion of TBL1 and treatment with
tegavivint reduce c-Myc protein expression in a post-transcriptional/β-catenin independent manner. We further
show that in DLBCL, TBL1 interacts with a Skp1/Cul1/F-Box (SCF) supercomplex, which controls the
proteasome-mediated degradation of critical pro-survival proteins such as c-

## Key facts

- **NIH application ID:** 11321531
- **Project number:** 5R01CA266682-05
- **Recipient organization:** OHIO STATE UNIVERSITY
- **Principal Investigator:** Lapo  Alinari
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $570,593
- **Award type:** 5
- **Project period:** 2022-04-01T00:00:00 → 2027-03-31T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11321531

## Citation

> US National Institutes of Health, RePORTER application 11321531, Targeting c-Myc stability in c-Myc overexpressing large B-cell lymphoma (5R01CA266682-05). Retrieved via AI Analytics 2026-07-08 from https://api.ai-analytics.org/grant/nih/11321531. Licensed CC0.

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