Abstract
More than fifteen years after their discovery, IDH mutations remain as intriguing as ever. Three mutational hotspots are described in different cancers, including glioma, chondrosarcoma, or hematological diseases, resulting in single amino acid substitutions in two of the IDH genes (IDH1R132, IDH2R172 and IDH2R140). Wild-type IDH1/2 catalyze the conversion of isocitrate into α-ketoglutarate (α-KG), and their mutations confer neomorphic activity to this metabolic enzyme, reducing α-KG to 2-hydroxyglutarate (2-HG). 2-HG is a potent inhibitor of several dioxygenases that normally use α-KG as a cofactor. Among them is the ten-eleven translocation (TET) family, which catalyzes the hydroxylation of methylated cytosine bases in the DNA. Mutations in epigenetic regulators, such as IDH, are commonly found in hematological malignancies including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML) and peripheral T cell lymphoma (PTCL), and especially angioimmunoblastic T cell lymphoma (AITL). Despite many advances, these hematologic diseases still have significant unmet medical needs, and require novel approaches to patient selection and therapy. IDH inhibitors are currently under investigation in MDS, AML and PTCL and have shown promise in early clinical trials for AML and MDS. However, not all IDH-mutant patients respond, and resistance frequently develops. Changes to epigenetic regulation and diversity driven by IDH1/2 mutations likely contribute to these effects, but our incomplete understanding of the underlying biology limits therapeutic intervention. Establishing the relationship between tumor genetics and human diseases in the context of IDH mutations is challenging. The distribution of the three hotspot mutations among the different pathologies is complex and not yet fully understood. An intriguing fact is that IDH2R140 mutation is exclusively found in myeloid malignancies. Furthermore, clinical data indicate that the co-mutational pattern of IDH1/2 mutations is associated differently in hematological disorders. For instance, IDH1/2 and TET2 mutations are essentially mutually exclusive in myeloid context but frequently co-occur in AITL, suggesting that their effects in specific cell types and disease contexts may differ. Understanding how IDH1/2 and TET2 mutations drive malignancy and why they cooperate differently in myeloid and lymphoid diseases can help distinguish common from specific mechanisms in myeloid and lymphoid compartments, revealing specific tumor cell vulnerabilities, which could be targeted to improve patient outcomes. The laboratory of Professor Mak has generated three strains of Idh knock-in mice, each bearing one of the three hotspot mutations and has assembled a multidisciplinary team in epigenetics and clinical investigation to explore their role and set the stage for further mechanistic insight into mutant IDH, both in myeloid or lymphoid contexts. 2-HG levels differ between the myeloid and lymphoid lineages of each strain and may explain the variations in the mutational spectrum associated with different cellular contexts. Even within the myeloid lineage, analyses of these three Idh-mutant mice suggest that these alleles produce phenotypes of varying severity, correlating with 2-HG levels, with Idh2R172 exhibiting the most severe phenotype. We showed that altered DNA and histone methylation; partially block hematopoietic cell differentiation at the hematopoietic stem cell/progenitor stage; resulting in a hematopoietic phenotype reminiscent of human MDS. Given the mutual exclusivity of IDH1/2 and TET2 mutations in myeloid neoplasms, it has been hypothesized that they converge on a common oncogenic pathway. However, in a first study, we demonstrated that mutant Idh1 impairs DNA repair via a mechanism independent of Tet2 at the stem cell stage. Then, in a second study, we showed that these alterations have distinct, and even opposite, effects on hematopoietic stem cells and progenitors. Epigenetic and single-cell transcriptomic analyses revealed that Idh2R172 and Tet2 mutations had diverging consequences. Our data argue against a simple equivalence of Idh1/2 and Tet2 mutations, and may help to explain some of the clinical differences between TET2- and IDH-mutant in a myeloid context. In PTCL, the neoplastic cells represent a minor part of the tumor, a truth that is even more pronounced in AITL, where the microenvironment frequently accounts for 90% of the tumoral mass. Using molecular and histological approaches, it has been shown that driving mutations, such as TET2, occur in hematopoietic stem cells, and are found in both malignant and non-malignant cells. On the other hand, others alterations, such as IDH2, occur in mature T cells, specifically in T follicular helper (TFH) cells, and are restrictive to malignant cells. Our team, in collaboration with a group of researchers led by Drs. Philippe Gaulard and François Lemonnier, demonstrated that TET and IDH mutations co-occur in TFH malignant cells. We showed increased levels of 2-HG both in tissue samples and serum of IDH2R172-mutated AITL patients, although these levels are lower than in AML patients. This difference could either be attributed to a lower tumor burden in AITL than in AML, or to the difference of the mutant enzyme ability to produce 2-HG based on the cellular context (myeloid cells versus lymphoid cells). Notably, IDH2 mutation without TET2 mutation is really rare in AITL. However, the reason why IDH2 mutation drives oncogenesis only in the presence of TET2 mutation is still not fully defined. After generating the first AITL mouse model mutated for Idh2 and Tet2, we demonstrated that the double mutant T cells produce more 2-HG than the single Idh2-mutated T cells, potentially resulting in a greater inhibition of αKG-dependent dioxygenases. This heightened ability to synthesize 2-HG could be linked to the altered metabolic gene expression programs in Tet2-mutated Tfh cells, although this hypothesis requires further confirmation. Ultimately, the combination of Idh2 and Tet2 mutations in TFH cells driving this disease undergoes extensive genetic and epigenetic reprogramming, mainly affecting their interactions with nearby cells in the microenvironment. Particularly, these mutations profoundly impact the crosstalk between neoplastic Tfh cells and the surrounding B cells, leading to the expansion of B and plasma cells in these mice, sometimes clonally. This recently discovered crosstalk among various immune cell types within the tumor microenvironment highlights the need to define how this cooperation occurs and what might disrupt its occurrence to forestall disease progression. Understanding the involvement of immune cells in the microenvironment in hematopoietic diseases holds the potential for significant advances in their treatment. In conclusion, genetically engineered mouse models serve as powerful tools to comprehend the implications of IDH mutations in myeloid or T cell biology. Our research shed new light on the mechanisms by which mutations in Idh1/2 and Tet2 drive the development and progression of leukemias and lymphomas. Through a multifaceted approach conducted in our genetically engineered mouse models, we have identified mutation-specific and disease-specific effects. This innovative approach has led to significant basic research discoveries which can now be evaluated in patient samples. These findings may help to select patients and devise additional treatment strategies using existing and investigational therapies, which can then be translated to preclinical testing.
Citation Format: Julie Leca. What IDH mouse models have taught us about hematological diseases, from leukemia to T cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr SY16-01.
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Apr 5, 2024
Hima Dhakal + 1
Open Access