# Investigating L-2-hydroxyglutarate in normal hematopoiesis and leukemogenesis

> **NIH NIH K08** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $177,336

## Abstract

PROJECT SUMMARY/ABSTRACT
Somatic mutations in the isocitrate dehydrogenase (IDH) enzymes contribute to the pathogenesis of acute
myeloid leukemia (AML) and other malignancies via production of the `oncometabolite' D-2-hydroxyglutarate
(D-2HG). D-2HG blocks differentiation of malignant cells by inhibiting α-ketoglutarate (αKG)-dependent
enzymes that regulate chromatin structure and gene expression. Small molecule inhibitors of mutant IDH
enzymes are emerging as promising new therapies for patients with AML, but their efficacy remains limited to
the subset of patients with IDH mutations. 2HG is a chiral molecule that can exist in either the D- or L-
enantiomer. Biochemical assays show that L-2HG functions much more potently than D-2HG as an inhibitor of
αKG-dependent chromatin-modifying enzymes, but biological sources and activities of L-2HG are poorly
understood. Preliminary data presented in this proposal describe a previously unknown metabolic pathway
where under conditions of oxygen limitation (a.k.a. hypoxia), cells potently and selectively produce L-2HG via
promiscuous enzymatic reduction of αKG by lactate dehydrogenase. L-2HG stabilizes hypoxia-inducible factor
1α (HIF1α) and increases repressive histone modifications characteristic of the undifferentiated/stem cell state.
The hypoxia-induced L-2HG pathway is active in primary embryonic and hematopoietic stem cells
(ESCs/HSCs) and leukemia cells, and experimental manipulations that increase L-2HG levels block the
differentiation of primary HSCs and ESCs. Normal blood stem cells and leukemia cells reside in and depend
on hypoxic regions of the bone marrow. Thus, L-2HG might represent a molecular mechanism whereby
hypoxic niches promote and maintain the immature state of normal blood stem cells and leukemia
stem/progenitor cells. This hypothesis will be rigorously tested by (1) using in vitro systems to elucidate the
effects of L-2HG on hematopoietic cell gene expression, epigenetic modifications, and differentiation, (2)
employing in vivo mouse models to determine if L-2HG influences normal or malignant hematopoiesis, and (3)
utilizing patient samples to determine if deregulated L-2HG metabolism is a feature of human leukemia. The
proposed investigations will expand the armamentarium of strategies to therapeutically target 2HG in cancer,
particularly for the large cohort of patients who lack IDH mutations. The applicant, Dr. Andrew Intlekofer, an
Assistant Attending with the Lymphoma Service at Memorial Sloan Kettering Cancer Center (MSKCC), has
outlined a 5-year career plan that builds upon his research background studying molecular mechanisms of cell
differentiation and his clinical training in oncology and malignant hematology. Dr. Intlekofer will conduct the
proposed research under the mentorship of Dr. Craig Thompson, an internationally recognized expert in
cancer metabolism with a strong track record of training successful physician scientists. MSKCC provides the
ideal institutional env...

## Key facts

- **NIH application ID:** 10003966
- **Project number:** 5K08CA201483-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Andrew Michael Intlekofer
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $177,336
- **Award type:** 5
- **Project period:** 2016-09-14 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003966

## Citation

> US National Institutes of Health, RePORTER application 10003966, Investigating L-2-hydroxyglutarate in normal hematopoiesis and leukemogenesis (5K08CA201483-05). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10003966. Licensed CC0.

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