Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Bofei Wang; Patrick K. Reville; Mhd Yousuf Yassouf; Fatima Z. Jelloul; Christopher Ly; Poonam N. Desai; Zhe Wang; Pamella Borges; Ivo Veletic; Enes Dasdemir; Jared K. Burks; Guilin Tang; Shengnan Guo; Araceli Isabella Garza; Cedric Nasnas; Nicole R. Vaughn; Natalia Baran; Qing Deng; Jairo Matthews; Preethi H. Gunaratne; Dinler A. Antunes; Suhendan Ekmekcioglu; Koji Sasaki; Miriam B. Garcia; Branko Cuglievan; Dapeng Hao; Naval Daver; Michael R. Green; Marina Konopleva; Andrew Futreal; Sean M. Post; Hussein A. Abbas

doi:10.1038/s41467-024-45916-6

Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

Bofei Wang, Patrick K. Reville, Mhd Yousuf Yassouf, Fatima Z. Jelloul, Christopher Ly, Poonam N. Desai, Zhe Wang, Pamella Borges, Ivo Veletic, Enes Dasdemir, Jared K. Burks, Guilin Tang, Shengnan Guo, Araceli Isabella Garza, Cedric Nasnas, Nicole R. Vaughn, Natalia Baran, Qing Deng, Jairo Matthews, Preethi H. GunaratneDinler A. Antunes, Suhendan Ekmekcioglu, Koji Sasaki, Miriam B. Garcia, Branko Cuglievan, Dapeng Hao, Naval Daver, Michael R. Green, Marina Konopleva, Andrew Futreal, Sean M. Post, Hussein A. Abbas

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Abstract

Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

Original language	English (US)
Article number	1821
Journal	Nature communications
Volume	15
Issue number	1
DOIs	https://doi.org/10.1038/s41467-024-45916-6
State	Published - Dec 2024

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Wang, B., Reville, P. K., Yassouf, M. Y., Jelloul, F. Z., Ly, C., Desai, P. N., Wang, Z., Borges, P., Veletic, I., Dasdemir, E., Burks, J. K., Tang, G., Guo, S., Garza, A. I., Nasnas, C., Vaughn, N. R., Baran, N., Deng, Q., Matthews, J., ... Abbas, H. A. (2024). Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies. Nature communications, 15(1), Article 1821. https://doi.org/10.1038/s41467-024-45916-6

Wang, B, Reville, PK, Yassouf, MY, Jelloul, FZ, Ly, C, Desai, PN, Wang, Z, Borges, P, Veletic, I, Dasdemir, E, Burks, JK , Tang, G, Guo, S, Garza, AI, Nasnas, C, Vaughn, NR, Baran, N , Deng, Q, Matthews, J, Gunaratne, PH, Antunes, DA, Ekmekcioglu, S , Sasaki, K , Garcia, MB , Cuglievan, B, Hao, D, Daver, N , Green, MR, Konopleva, M, Futreal, A , Post, SM & Abbas, HA 2024, 'Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies', Nature communications, vol. 15, no. 1, 1821. https://doi.org/10.1038/s41467-024-45916-6

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title = "Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies",

abstract = "Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.",

author = "Bofei Wang and Reville, {Patrick K.} and Yassouf, {Mhd Yousuf} and Jelloul, {Fatima Z.} and Christopher Ly and Desai, {Poonam N.} and Zhe Wang and Pamella Borges and Ivo Veletic and Enes Dasdemir and Burks, {Jared K.} and Guilin Tang and Shengnan Guo and Garza, {Araceli Isabella} and Cedric Nasnas and Vaughn, {Nicole R.} and Natalia Baran and Qing Deng and Jairo Matthews and Gunaratne, {Preethi H.} and Antunes, {Dinler A.} and Suhendan Ekmekcioglu and Koji Sasaki and Garcia, {Miriam B.} and Branko Cuglievan and Dapeng Hao and Naval Daver and Green, {Michael R.} and Marina Konopleva and Andrew Futreal and Post, {Sean M.} and Abbas, {Hussein A.}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

doi = "10.1038/s41467-024-45916-6",

language = "English (US)",

volume = "15",

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T1 - Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

AU - Wang, Bofei

AU - Reville, Patrick K.

AU - Yassouf, Mhd Yousuf

AU - Jelloul, Fatima Z.

AU - Ly, Christopher

AU - Desai, Poonam N.

AU - Wang, Zhe

AU - Borges, Pamella

AU - Veletic, Ivo

AU - Dasdemir, Enes

AU - Burks, Jared K.

AU - Tang, Guilin

AU - Guo, Shengnan

AU - Garza, Araceli Isabella

AU - Nasnas, Cedric

AU - Vaughn, Nicole R.

AU - Baran, Natalia

AU - Deng, Qing

AU - Matthews, Jairo

AU - Gunaratne, Preethi H.

AU - Antunes, Dinler A.

AU - Ekmekcioglu, Suhendan

AU - Sasaki, Koji

AU - Garcia, Miriam B.

AU - Cuglievan, Branko

AU - Hao, Dapeng

AU - Daver, Naval

AU - Green, Michael R.

AU - Konopleva, Marina

AU - Futreal, Andrew

AU - Post, Sean M.

AU - Abbas, Hussein A.

PY - 2024/12

Y1 - 2024/12

N2 - Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

AB - Interferon gamma (IFNγ) is a critical cytokine known for its diverse roles in immune regulation, inflammation, and tumor surveillance. However, while IFNγ levels were elevated in sera of most newly diagnosed acute myeloid leukemia (AML) patients, its complex interplay in AML remains insufficiently understood. We aim to characterize these complex interactions through comprehensive bulk and single-cell approaches in bone marrow of newly diagnosed AML patients. We identify monocytic AML as having a unique microenvironment characterized by IFNγ producing T and NK cells, high IFNγ signaling, and immunosuppressive features. IFNγ signaling score strongly correlates with venetoclax resistance in primary AML patient cells. Additionally, IFNγ treatment of primary AML patient cells increased venetoclax resistance. Lastly, a parsimonious 47-gene IFNγ score demonstrates robust prognostic value. In summary, our findings suggest that inhibiting IFNγ is a potential treatment strategy to overcoming venetoclax resistance and immune evasion in AML patients.

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Comprehensive characterization of IFNγ signaling in acute myeloid leukemia reveals prognostic and therapeutic strategies

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