Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value
The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid...
| Main Authors: | , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2022-11-01
|
| Series: | International Journal of Molecular Sciences |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1422-0067/23/23/14885 |
| _version_ | 1797463100382773248 |
|---|---|
| author | Simona Pagliuca Carmelo Gurnari Keman Zhang Tariq Kewan Waled Bahaj Minako Mori Ishani Nautiyal Marie Thérèse Rubio Francesca Ferraro Jaroslaw P. Maciejewski Li Wang Valeria Visconte |
| author_facet | Simona Pagliuca Carmelo Gurnari Keman Zhang Tariq Kewan Waled Bahaj Minako Mori Ishani Nautiyal Marie Thérèse Rubio Francesca Ferraro Jaroslaw P. Maciejewski Li Wang Valeria Visconte |
| author_sort | Simona Pagliuca |
| collection | DOAJ |
| description | The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with <i>NPM1</i> mutations regardless of the presence of <i>FLT3</i> lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and <i>NPM1</i> mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance. |
| first_indexed | 2024-03-09T17:45:51Z |
| format | Article |
| id | doaj.art-c8ff4aaff6234a368bc013e735c0953b |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:45:51Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-c8ff4aaff6234a368bc013e735c0953b2023-11-24T11:09:41ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231488510.3390/ijms232314885Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic ValueSimona Pagliuca0Carmelo Gurnari1Keman Zhang2Tariq Kewan3Waled Bahaj4Minako Mori5Ishani Nautiyal6Marie Thérèse Rubio7Francesca Ferraro8Jaroslaw P. Maciejewski9Li Wang10Valeria Visconte11Translational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USAService d’hématologie, Hôpital Brabois, CHRU Nancy and CNRS UMR 7365 IMoPa, Biopôle de l’Université de Lorraine, 54500 Vandoeuvre les Nancy, FranceDivision of Oncology, Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USATranslational Hematology and Oncology Research Department of Cleveland Clinic, Cleveland, OH 44106, USAThe V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with <i>NPM1</i> mutations regardless of the presence of <i>FLT3</i> lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and <i>NPM1</i> mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance.https://www.mdpi.com/1422-0067/23/23/14885VISTAAML immunotherapyimmune escapeimmune checkpoint regulationNPM1 |
| spellingShingle | Simona Pagliuca Carmelo Gurnari Keman Zhang Tariq Kewan Waled Bahaj Minako Mori Ishani Nautiyal Marie Thérèse Rubio Francesca Ferraro Jaroslaw P. Maciejewski Li Wang Valeria Visconte Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value International Journal of Molecular Sciences VISTA AML immunotherapy immune escape immune checkpoint regulation NPM1 |
| title | Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value |
| title_full | Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value |
| title_fullStr | Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value |
| title_full_unstemmed | Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value |
| title_short | Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia: Insights into Its Prognostic Value |
| title_sort | comprehensive transcriptomic analysis of vista in acute myeloid leukemia insights into its prognostic value |
| topic | VISTA AML immunotherapy immune escape immune checkpoint regulation NPM1 |
| url | https://www.mdpi.com/1422-0067/23/23/14885 |
| work_keys_str_mv | AT simonapagliuca comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT carmelogurnari comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT kemanzhang comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT tariqkewan comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT waledbahaj comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT minakomori comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT ishaninautiyal comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT mariethereserubio comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT francescaferraro comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT jaroslawpmaciejewski comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT liwang comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue AT valeriavisconte comprehensivetranscriptomicanalysisofvistainacutemyeloidleukemiainsightsintoitsprognosticvalue |