Gain-of-function mutations in isocitrate dehydrogenase 1 (
IDH1) are key drivers of hematopoietic malignancies. Although these mutations are most commonly associated with myeloid diseases, they also occur in malignancies of the T-cell lineage. To investigate their role in these diseases and provide tractable disease models for further investigation, we analyzed the T-cell compartment in a conditional knock-in (KI) mouse model of mutant
Idh1. We observed the development of a spontaneous T-cell acute lymphoblastic leukemia (T-ALL) in these animals. The disease was transplantable and maintained expression of mutant IDH1. Whole-exome sequencing revealed the presence of a spontaneous activating mutation in
Notch1, one of the most common mutations in human T-ALL, suggesting
Idh1 mutations may have the capacity to cooperate with
Notch1 to drive T-ALL. To further investigate the
Idh1 mutation as an oncogenic driver in the T-cell lineage, we crossed
Idh1-KI mice with conditional
Trp53 null mice, a well-characterized model of T-cell malignancy, and found that T-cell lymphomagenesis was accelerated in mice bearing both mutations. Because both IDH1 and p53 are known to affect cellular metabolism, we compared the requirements for glucose and glutamine in cells derived from these tumors and found that cells bearing the
Idh1 mutation have an increased dependence on both glucose and glutamine. These data suggest that mutant IDH1 contributes to malignancy in the T-cell lineage and may alter the metabolic profile of malignant T cells.Somatic mutations in isocitrate dehydrogenase 1 (
IDH1) are frequently observed in a number of malignancies, including glioma, cholangiocarcinoma, chondrosarcoma, and several hematological malignancies (
1). IDH1 is a cytoplasmic enzyme that catalyzes the NADP-dependent conversion of isocitrate to α-ketoglutarate (αKG). Mutations in IDH1 at arginine 132 (R132) cause an enzymatic gain of function that results in the NADPH-dependent conversion of αKG to
d-2-hydroxyglutarate (2HG) (
2). This metabolite is normally maintained at very low levels in cells and tissues and is not part of any known productive metabolic pathway. However, in cells and tissues of patients with IDH1 mutant tumors, 2HG builds up to high levels and is thought to contribute to tumorigenesis by inhibiting a class of αKG-dependent enzymes (
1). The precise effects important for driving tumorigenesis downstream of
IDH1 mutations are not fully understood and may differ between disease states.In the hematopoietic system,
IDH1 mutations are most often associated with myeloid diseases, where they are commonly found in myelodysplastic syndrome and acute myeloid leukemia (
3). However,
IDH1 mutations are also found in a small proportion of adult T-cell acute lymphoblastic leukemia (T-ALL) (
4,
5). T-ALL is an aggressive malignancy of developing T cells and is responsible for ∼25% of adult ALL (
6,
7). T-ALL is thought to arise via a multistep process of oncogenic mutation that leads to the transformation of immature T cells. The genetic landscape of the disease has been characterized, and a large number of driver mutations have been identified (
6). The most common genetic feature of T-ALL is the presence of activating mutations in
Notch1, which are present in more than 50% of patients (
8). Interestingly,
IDH1 mutations seem to be confined to a subset of adult patients with T-ALL bearing an immature T-cell gene expression signature and harboring other oncogenic mutations in genes more commonly associated with myeloid malignancy, including
Flt3 and
DNMT3A (
4,
9). This subset of T-ALL has recently been recognized as a distinct disease entity called early T-cell precursor T-ALL and is associated with therapy resistance and a particularly poor outcome (
10). The role of
IDH1 mutations in this subset of T-ALL is not understood.Using a myeloid lineage-specific conditional
Idh1-R132-KI mouse model, we previously showed that mutant IDH1 partially blocks differentiation and produces a hematopoietic phenotype similar to human myelodysplastic syndrome (
11). In this study, we crossed the
Idh1-R132-KI mouse with
Vav-cre animals to introduce the IDH1 R132 mutation into the entire hematopoietic system to investigate the role of
Idh1 mutations in T-cell malignancy.
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