An IDO1-related immune gene signature predicts overall survival in acute myeloid leukemia

Abstract

The contribution of the bone marrow (BM) immune microenvironment (TME) to acute myeloid leukemia (AML) development is well-known, but its prognostic significance is still elusive. Indoleamine 2,3-dioxygenase 1 (IDO1), which is negatively regulated by the BIN1 proto-oncogene, is an interferon (IFN)-γ-inducible mediator of immune tolerance. With the aim to develop a prognostic IDO1-based immune gene signature, biological and clinical data of 732 patients with newly diagnosed, non-promyelocytic AML were retrieved from public datasets and analyzed using established computational pipelines. Targeted transcriptomic profiles of 24 diagnostic BM samples were analyzed using the NanoString's nCounter platform. BIN1 and IDO1 were inversely correlated and individually predicted overall survival. PLXNC1, a semaphorin receptor involved in inflammation and immune response, was the IDO1-interacting gene retaining the strongest prognostic value. The incorporation of PLXNC1 into the 2-gene IDO1-BIN1 score gave rise to a powerful immune gene signature predicting survival, especially in patients receiving chemotherapy. The top differentially expressed genes between IDO1low and IDO-1high and between PLXNC1low and PLXNC1 high cases further improved the prognostic value of IDO1 providing a 7 and 10-gene immune signature, highly predictive of survival and correlating with AML mutational status at diagnosis. Taken together, our data indicate that IDO1 is pivotal for the construction of an immune gene signature predictive of survival in AML patients. Given the emerging role of immunotherapies for AML, our findings support the incorporation of immune biomarkers into current AML classification and prognostication algorithms.

Emerging Bone Marrow Microenvironment-Driven Mechanisms of Drug Resistance in Acute Myeloid Leukemia: Tangle or Chance?

“…IDO1 activity increases T cell apoptosis, reduces T cell proliferation, and induces Tregs ( Figure 2 B) [ 140 , 141 ]. IDO1 expression in AML cells has been correlated to poor clinical outcomes [ 142 , 143 ].…”

“…IDO1 exerts immune-regulating activity in different settings, including AML [ 194 ]. AML cells, but not normal HSCs, expressed IDO1 [ 195 ], which mediates immune tolerance [ 132 ] and correlates with a poor clinical outcome, as described above [ 142 , 143 ]. MSCs, including those isolated from myelodysplastic syndrome (MDS) and AML patients, up-regulate IDO1 following pro-inflammatory stimulation [ 86 , 193 ].…”

Tumor Microenvironment in Acute Myeloid Leukemia: Adjusting Niches

“…They can also produce reactive oxygen species (62) and indolamine-2, 3-dioxygenase (IDO), which both promote differentiation towards Tregs (63). Just recently, a study by Ragaini et al demonstrated that an IDO1-related immune gene signature predicts overall survival in AML (64). Another target to induce T-cell anergy is T-cell immunoglobulin and mucin domain 3 (TIM3), which binds to and is activated by galectin-9, the latter being highly expressed on AML blasts, which leads to an activation of several downstream signaling pathways such as the MAPK/ERK, PI3K-and AKT (65).…”

Regulation of hematopoietic and leukemia stem cells by regulatory T cells

“…In the BM of newly diagnosed AML patients, high IDO expression in MSCs was associated with elevated levels of Tregs. Furthermore, an IDO1-related immune gene signature has been identified as a negative predictor for overall survival in AML ( 99 ). Similarly, MSCs derived from Fanconi anaemia patients with AML secrete high levels of prostaglandins which resulted in Treg induction and subsequent inhibition of CD8 + CTLs ( 100 ).…”