TY - JOUR
T1 - Comprehensive Transcriptomic Analysis of VISTA in Acute Myeloid Leukemia
T2 - Insights into Its Prognostic Value
AU - Pagliuca, Simona
AU - Gurnari, Carmelo
AU - Zhang, Keman
AU - Kewan, Tariq
AU - Bahaj, Waled
AU - Mori, Minako
AU - Nautiyal, Ishani
AU - Rubio, Marie Thérèse
AU - Ferraro, Francesca
AU - Maciejewski, Jaroslaw P.
AU - Wang, Li
AU - Visconte, Valeria
N1 - Funding Information:
We thank the following sources of funding: the Vera and Joseph Dresner Foundation–MDS (to V.V.), R01CA164225, R01CA223804, American Cancer Society Research Scholar Grant RSG-18-045-01–LIB, R21 CA258618, the Cancer Research Institute Clinic and Laboratory Integration Program Award (to L.W.), R01HL118281, R01HL123904, R01HL132071, R35HL135795 (to J.P.M.), the Italian Society of Hematology, Italian Society of Experimental Hematology, Fondation ARC pour la Recherche sur le Cancer, Philippe Foundation, MDS Foundation (to S.P.), The American–Italian Cancer Foundation (to C.G.), and the K12CA167540 and K08CA252632 (to F.F).
Publisher Copyright:
© 2022 by the authors.
PY - 2022/12
Y1 - 2022/12
N2 - 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 NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 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.
AB - 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 NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 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.
KW - AML immunotherapy
KW - NPM1
KW - VISTA
KW - immune checkpoint regulation
KW - immune escape
UR - http://www.scopus.com/inward/record.url?scp=85143690730&partnerID=8YFLogxK
U2 - 10.3390/ijms232314885
DO - 10.3390/ijms232314885
M3 - Article
C2 - 36499220
AN - SCOPUS:85143690730
SN - 1661-6596
VL - 23
JO - International Journal of Molecular Sciences
JF - International Journal of Molecular Sciences
IS - 23
M1 - 14885
ER -