# The Role of DLST in Leukemogenesis

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $392,723

## Abstract

PROJECT SUMMARY
Despite treatment improvements, leukemia-associated mortality is still high owing to drug resistance and
disease relapse. Metabolic reprogramming is a hallmark of cancer, and represents an exciting new area of
targeted therapy. Therefore, identification of the key enzyme responsible for metabolic reprogramming and
elucidation of its mechanisms of action in treatment-resistant leukemic cells could lead to novel therapeutic
strategies against the unique metabolic dependence of these cancer cells. We recently reported that
dihydrolipoamide S-succinyltransferase (DLST) serves as a critical metabolic “oncorequisite” enzyme in MYC-
driven leukemogenesis. MYC-dependent T-acute lymphoblastic leukemia (T-ALL) cells reprogram metabolism
by stabilizing DLST protein, and rely heavily on its elevated levels for proliferation and survival. Heterozygous
loss of dlst in zebrafish does not impair development yet significantly delays the onset of MYC-induced T-ALL
that resembles a major subtype of human disease with poor prognosis. DLST is a transferase in the
tricarboxylic acid (TCA) cycle and mediates the conversion of α-ketoglutarate (α-KG) to succinyl-CoA. α-KG is
a key cycle intermediate that simultaneously functions as an obligatory cofactor for α-KG-dependent
dioxygenases (α-KGDO, e.g., demethylases), thus linking cellular metabolism with epigenetic controls of the
cell. We hypothesize that: DLST protein stabilization accelerates α-KG conversion, enhances TCA
cycle function, and suppresses α-KGDO activities, thus promoting leukemic cell proliferation and
survival. In Aim 1 of this application we will apply genetic, pharmacological and biochemical approaches to
determine the mechanisms by which DLST is stabilized in MYC-overexpressing T-ALL cells and identify novel
DLST interactors including its E3 ligase(s). The zebrafish T-ALL model will then be utilized to define the role of
key DLST regulators/interactors in T-ALL pathogenesis. In Aim 2, we will combine the analyses of the in vivo
zebrafish model and human T-ALL cells to identify the biochemical and epigenetic changes associated with
DLST inactivation, as well as functionally characterize key α-KGDO regulated by DLST in T-ALL pathogenesis.
In Aim 3, we will investigate the targetability and compensatory pathways of DLST in relapsed/refractory T-ALL
by using our newly identified DLST inhibitor and in vivo animal models including murine patient-derived
xenografts. The innovation of this application lies in the study of DLST as a novel “oncorequisite” enzyme
that regulates both metabolism and epigenetic status of the cell in a physiologically relevant in vivo zebrafish
system. Indeed, this innovative system has enabled us to identify MYC and AMP-activated protein kinase as
regulators for DLST and isocitrate dehydrogenase 2 as its compensatory gene. This research is significant in
that it will deepen our understanding of leukemia pathogenesis and cancer metabolism, as well as the
metabolo-epi...

## Key facts

- **NIH application ID:** 9982277
- **Project number:** 5R01CA215059-03
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Hui Feng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $392,723
- **Award type:** 5
- **Project period:** 2018-08-07 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9982277

## Citation

> US National Institutes of Health, RePORTER application 9982277, The Role of DLST in Leukemogenesis (5R01CA215059-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9982277. Licensed CC0.

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