# Molecular Characterization of elF4B

> **NIH VA I01** · VA VETERANS ADMINISTRATION HOSPITAL · 2024 · —

## Abstract

Diffuse large B-cell lymphoma (DLBCL) represents the most common subtype of non-Hodgkin lymphoma (NHL),
accounting for about 40% of all newly diagnosed cases in the United States. Despite the relative success of
upfront R-CHOP therapy, the frequent occurrence of relapsed/refractory cases and the limitations to treating
patients with co-morbidities has provided the impetus to discover novel actionable molecular targets to improve
outcomes. Two of these rewired metabolic gene signatures of fatty acid synthase (FASN) & LKB1 (Liver Kinase
B1) and the protein translational machinery components are emerging as putative candidates for therapeutic
intervention in DLBCL. Supported by robust data from several independent laboratories, identification of unique
molecular, metabolic signatures such as perturbation in fatty acid metabolism and depletion of LKB1 signaling
are associated with DLBCL survival and underlying lymphomagenic mechanism(s). However, limited success in
the clinical and pre-clinical arena targeting FASN and LKB1 due to pharmacological limitations has motivated
investigators to identify downstream effectors, providing alternative actionable candidates with applicability in
suppressing heterogenous DLCBL tumor growth. To point, exciting preliminary data from our lab identified eIF4B
(Eukaryotic initiation factor 4B), a critical translational machinery component, is activated by enhanced FASN
activity. It is broadly accepted that unregulated FASN activity is strongly correlated with multi-drug resistance, a
prominent feature observed in patients with R-CHOP resistant disease. Further, we reported that FASN (an
essential enzyme in the altered metabolome of DLBCL) directly regulates PI3K/S6Kinase mediated USP11
(Ubiquitin Specific Protease 11) driven eIF4B activity, which enhances oncogene expression in DLBCL.
Unfortunately, there are no available murine models to delineate their physiological roles in B-cell
development and homeostasis. Another critical question raised from our earlier published work was interrogating
the molecular partners associated with the eIF4B ubiquitination machinery. Preliminary findings revealed
PARK2 as a potential E3 Ligase, polyubiquitinating eIF4B. Further expanding our observation of the rewired
metabolic impact on eIF4B driven translation, we found that LKB1 phosphorylates eIF4B, hindering eIF4B-
sensitive gene expression. To address these findings in-depth, we will pursue the following three specific
aims: Specific Aim 1: Define the molecular role of PARK2 in polyubiquitination of eIF4B and DLBCL
proliferation, Specific Aim 2: Determine the impact of LKB1 activity on eIF4B-dependent translation and
Specific Aim 3: Determine the molecular dependence of eIF4B in B-cells. While we have acquired
compelling cell-based data demonstrating the functional importance of eIF4B in DLBCL, we will expand our
mechanistic understanding by characterizing the physiological inputs of eIF4B in B-cells using engineered mouse
model...

## Key facts

- **NIH application ID:** 10721345
- **Project number:** 5I01BX005789-02
- **Recipient organization:** VA VETERANS ADMINISTRATION HOSPITAL
- **Principal Investigator:** Ronald B Gartenhaus
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2024
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2022-10-01 → 2027-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10721345

## Citation

> US National Institutes of Health, RePORTER application 10721345, Molecular Characterization of elF4B (5I01BX005789-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10721345. Licensed CC0.

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