A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML

Bo Rui Chen; Anagha Deshpande; Karina Barbosa; Maria Kleppe; Xue Lei; Narayana Yeddula; Pablo Sánchez Vela; Alexandre Rosa Campos; Robert J. Wechsler-Reya; Anindya Bagchi; Soheil Meshinchi; Connie Eaves; Irmela Jeremias; Torsten Haferlach; David A. Frank; Ze'ev Ronai; Sumit Chanda; Scott A. Armstrong; Peter D. Adams; Ross L. Levine; Aniruddha J. Deshpande

doi:10.1182/blood.2020009023

A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML

Bo Rui Chen, Anagha Deshpande, Karina Barbosa, Maria Kleppe, Xue Lei, Narayana Yeddula, Pablo Sánchez Vela, Alexandre Rosa Campos, Robert J. Wechsler-Reya, Anindya Bagchi, Soheil Meshinchi, Connie Eaves, Irmela Jeremias, Torsten Haferlach, David A. Frank, Ze'ev Ronai, Sumit Chanda, Scott A. Armstrong, Peter D. Adams, Ross L. LevineAniruddha J. Deshpande

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	3403-3415
Number of pages	13
Journal	Blood
Volume	137
Issue number	24
DOIs	https://doi.org/10.1182/blood.2020009023
State	Published - 17 Jun 2021
Externally published	Yes

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Chen, B. R., Deshpande, A., Barbosa, K., Kleppe, M., Lei, X., Yeddula, N., Vela, P. S., Campos, A. R., Wechsler-Reya, R. J., Bagchi, A., Meshinchi, S., Eaves, C., Jeremias, I., Haferlach, T., Frank, D. A., Ronai, Z., Chanda, S., Armstrong, S. A., Adams, P. D., ... Deshpande, A. J. (2021). A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML. Blood, 137(24), 3403-3415. https://doi.org/10.1182/blood.2020009023

@article{d846e1ce2f5f4d45a0ffda9dca86beeb,

title = "A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML",

abstract = "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.",

author = "Chen, {Bo Rui} and Anagha Deshpande and Karina Barbosa and Maria Kleppe and Xue Lei and Narayana Yeddula and Vela, {Pablo S{\'a}nchez} and Campos, {Alexandre Rosa} and Wechsler-Reya, {Robert J.} and Anindya Bagchi and Soheil Meshinchi and Connie Eaves and Irmela Jeremias and Torsten Haferlach and Frank, {David A.} and Ze'ev Ronai and Sumit Chanda and Armstrong, {Scott A.} and Adams, {Peter D.} and Levine, {Ross L.} and Deshpande, {Aniruddha J.}",

note = "Publisher Copyright: {\textcopyright} 2021 American Society of Hematology",

year = "2021",

month = jun,

day = "17",

doi = "10.1182/blood.2020009023",

language = "English",

volume = "137",

pages = "3403--3415",

journal = "Blood",

issn = "0006-4971",

publisher = "Elsevier BV",

number = "24",

}

Chen, BR, Deshpande, A, Barbosa, K, Kleppe, M, Lei, X, Yeddula, N, Vela, PS, Campos, AR, Wechsler-Reya, RJ, Bagchi, A, Meshinchi, S, Eaves, C, Jeremias, I, Haferlach, T, Frank, DA, Ronai, Z, Chanda, S, Armstrong, SA, Adams, PD, Levine, RL & Deshpande, AJ 2021, 'A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML', Blood, vol. 137, no. 24, pp. 3403-3415. https://doi.org/10.1182/blood.2020009023

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.

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 -

A JAK/STAT-mediated inflammatory signaling cascade drives oncogenesis in AF10-rearranged AML

Abstract

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