RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells

Ulrike Höckendorf; Monica Yabal; Tobias Herold; Enkhtsetseg Munkhbaatar; Stephanie Rott; Stefanie Jilg; Johanna Kauschinger; Giovanni Magnani; Florian Reisinger; Michael Heuser; Hans Kreipe; Karl Sotlar; Thomas Engleitner; Roland Rad; Wilko Weichert; Christian Peschel; Jürgen Ruland; Mathias Heikenwalder; Karsten Spiekermann; Julia Slotta-Huspenina; Olaf Groß; Philipp J. Jost

doi:10.1016/j.ccell.2016.06.002

RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells

Ulrike Höckendorf, Monica Yabal, Tobias Herold, Enkhtsetseg Munkhbaatar, Stephanie Rott, Stefanie Jilg, Johanna Kauschinger, Giovanni Magnani, Florian Reisinger, Michael Heuser, Hans Kreipe, Karl Sotlar, Thomas Engleitner, Roland Rad, Wilko Weichert, Christian Peschel, Jürgen Ruland, Mathias Heikenwalder, Karsten Spiekermann, Julia Slotta-HuspeninaOlaf Groß, Philipp J. Jost

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Abstract

Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1^−/−, Pycard^–/–, and Tnfr1/2^−/− mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.

Original language	English
Pages (from-to)	75-91
Number of pages	17
Journal	Cancer Cell
Volume	30
Issue number	1
DOIs	https://doi.org/10.1016/j.ccell.2016.06.002
State	Published - 11 Jul 2016

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Höckendorf, U., Yabal, M., Herold, T., Munkhbaatar, E., Rott, S., Jilg, S., Kauschinger, J., Magnani, G., Reisinger, F., Heuser, M., Kreipe, H., Sotlar, K., Engleitner, T., Rad, R., Weichert, W., Peschel, C., Ruland, J., Heikenwalder, M., Spiekermann, K., ... Jost, P. J. (2016). RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells. Cancer Cell, 30(1), 75-91. https://doi.org/10.1016/j.ccell.2016.06.002

@article{71a6041dddfd4d1aa707fd95d93e2a8b,

title = "RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells",

abstract = "Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1−/−, Pycard–/–, and Tnfr1/2−/− mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.",

author = "Ulrike H{\"o}ckendorf and Monica Yabal and Tobias Herold and Enkhtsetseg Munkhbaatar and Stephanie Rott and Stefanie Jilg and Johanna Kauschinger and Giovanni Magnani and Florian Reisinger and Michael Heuser and Hans Kreipe and Karl Sotlar and Thomas Engleitner and Roland Rad and Wilko Weichert and Christian Peschel and J{\"u}rgen Ruland and Mathias Heikenwalder and Karsten Spiekermann and Julia Slotta-Huspenina and Olaf Gro{\ss} and Jost, {Philipp J.}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = jul,

day = "11",

doi = "10.1016/j.ccell.2016.06.002",

language = "English",

volume = "30",

pages = "75--91",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

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Höckendorf, U, Yabal, M, Herold, T, Munkhbaatar, E, Rott, S, Jilg, S, Kauschinger, J, Magnani, G, Reisinger, F, Heuser, M, Kreipe, H, Sotlar, K, Engleitner, T, Rad, R , Weichert, W , Peschel, C, Ruland, J, Heikenwalder, M, Spiekermann, K, Slotta-Huspenina, J, Groß, O & Jost, PJ 2016, 'RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells', Cancer Cell, vol. 30, no. 1, pp. 75-91. https://doi.org/10.1016/j.ccell.2016.06.002

TY - JOUR

T1 - RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells

AU - Höckendorf, Ulrike

AU - Yabal, Monica

AU - Herold, Tobias

AU - Munkhbaatar, Enkhtsetseg

AU - Rott, Stephanie

AU - Jilg, Stefanie

AU - Kauschinger, Johanna

AU - Magnani, Giovanni

AU - Reisinger, Florian

AU - Heuser, Michael

AU - Kreipe, Hans

AU - Sotlar, Karl

AU - Engleitner, Thomas

AU - Rad, Roland

AU - Weichert, Wilko

AU - Peschel, Christian

AU - Ruland, Jürgen

AU - Heikenwalder, Mathias

AU - Spiekermann, Karsten

AU - Slotta-Huspenina, Julia

AU - Groß, Olaf

AU - Jost, Philipp J.

PY - 2016/7/11

Y1 - 2016/7/11

N2 - Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1−/−, Pycard–/–, and Tnfr1/2−/− mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.

AB - Since acute myeloid leukemia (AML) is characterized by the blockade of hematopoietic differentiation and cell death, we interrogated RIPK3 signaling in AML development. Genetic loss of Ripk3 converted murine FLT3-ITD-driven myeloproliferation into an overt AML by enhancing the accumulation of leukemia-initiating cells (LIC). Failed inflammasome activation and cell death mediated by tumor necrosis factor receptor caused this accumulation of LIC exemplified by accelerated leukemia onset in Il1r1−/−, Pycard–/–, and Tnfr1/2−/− mice. RIPK3 signaling was partly mediated by mixed lineage kinase domain-like. This link between suppression of RIPK3, failed interleukin-1β release, and blocked cell death was supported by significantly reduced RIPK3 in primary AML patient cohorts. Our data identify RIPK3 and the inflammasome as key tumor suppressors in AML.

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U2 - 10.1016/j.ccell.2016.06.002

DO - 10.1016/j.ccell.2016.06.002

M3 - Article

C2 - 27411587

AN - SCOPUS:84979732790

SN - 1535-6108

VL - 30

SP - 75

EP - 91

JO - Cancer Cell

JF - Cancer Cell

IS - 1

ER -

RIPK3 Restricts Myeloid Leukemogenesis by Promoting Cell Death and Differentiation of Leukemia Initiating Cells

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