TY - JOUR
T1 - A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML
AU - Chen, Bo Rui
AU - Deshpande, Anagha
AU - Barbosa, Karina
AU - Kleppe, Maria
AU - Lei, Xue
AU - Yeddula, Narayana
AU - Vela, Pablo Sánchez
AU - Campos, Alexandre Rosa
AU - Wechsler-Reya, Robert J.
AU - Bagchi, Anindya
AU - Meshinchi, Soheil
AU - Eaves, Connie
AU - Jeremias, Irmela
AU - Haferlach, Torsten
AU - Frank, David A.
AU - Ronai, Ze'ev
AU - Chanda, Sumit
AU - Armstrong, Scott A.
AU - Adams, Peter D.
AU - Levine, Ross L.
AU - Deshpande, Aniruddha J.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) National Cancer Institute grants R00 CA154880 and P30 CA030199, the Rally Foundation for Childhood Cancer Research and the Luke Tatsu Johnson Foundation under award number 19YIN45, an Emerging Scientist Award from the Children's Cancer Research Fund, and the V Foundation for Cancer Research (TVF) under award number DVP2019-015. This work was also supported by the Lady Tata Foundation (A.D.) and Memorial Sloan Kettering Cancer Center (MSKCC) support grant P30 CA008748 from the NIH National Cancer Institute. R.L.L. was supported by NIH National Cancer Institute grant R35 CA197594 and by Specialized Center of Research (SCOR) grants from the Leukemia & Lymphoma Society. S.A.A. was supported by NIH National Cancer Institute grants CA176745, CA206963, CA204639, and CA066996 and by the Leukemia & Lymphoma Society.
Funding Information:
The authors gratefully acknowledge Brian James from the Sanford Burnham Prebys Medical Discovery Institute (SBP) genomic core, Yoav Altman from the SBP Flow Cytometry Core, and Guillermina Garcia from SBP histology core for their excellent support with genomic, flow sorting, and histology experiments, respectively. The authors would also like to thank Warren Pear for kindly providing the MSCV-Trib2 plasmid. This work was supported by National Institutes of Health (NIH) National Cancer Institute grants R00 CA154880 and P30 CA030199, the Rally Foundation for Childhood Cancer Research and the Luke Tatsu Johnson Foundation under award number 19YIN45, an Emerging Scientist Award from the Children's Cancer Research Fund, and the V Foundation for Cancer Research (TVF) under award number DVP2019-015. This work was also supported by the Lady Tata Foundation (A.D.) and Memorial Sloan Kettering Cancer Center (MSKCC) support grant P30 CA008748 from the NIH National Cancer Institute. R.L.L. was supported by NIH National Cancer Institute grant R35 CA197594 and by Specialized Center of Research (SCOR) grants from the Leukemia & Lymphoma Society. S.A.A. was supported by NIH National Cancer Institute grants CA176745, CA206963, CA204639, and CA066996 and by the Leukemia & Lymphoma Society.
Publisher Copyright:
© 2021 American Society of Hematology
PY - 2021/6/17
Y1 - 2021/6/17
N2 - Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
AB - Leukemias bearing fusions of the AF10/MLLT10 gene are associated with poor prognosis, and therapies targeting these fusion proteins (FPs) are lacking. To understand mechanisms underlying AF10 fusion-mediated leukemogenesis, we generated inducible mouse models of acute myeloid leukemia (AML) driven by the most common AF10 FPs, PICALM/CALM-AF10 and KMT2A/MLL-AF10, and performed comprehensive characterization of the disease using transcriptomic, epigenomic, proteomic, and functional genomic approaches. Our studies provide a detailed map of gene networks and protein interactors associated with key AF10 fusions involved in leukemia. Specifically, we report that AF10 fusions activate a cascade of JAK/STAT-mediated inflammatory signaling through direct recruitment of JAK1 kinase. Inhibition of the JAK/STAT signaling by genetic Jak1 deletion or through pharmacological JAK/STAT inhibition elicited potent antioncogenic effects in mouse and human models of AF10 fusion AML. Collectively, our study identifies JAK1 as a tractable therapeutic target in AF10-rearranged leukemias.
UR - http://www.scopus.com/inward/record.url?scp=85108583209&partnerID=8YFLogxK
U2 - 10.1182/blood.2020009023
DO - 10.1182/blood.2020009023
M3 - Article
C2 - 33690798
AN - SCOPUS:85108583209
SN - 0006-4971
VL - 137
SP - 3403
EP - 3415
JO - Blood
JF - Blood
IS - 24
ER -