The NLRP3/eIF2 axis promotes leukemic blasts survival and disease progression in acute myeloid leukemia

  • Unger, M. S. (Speaker)
  • Michela Luciano (Speaker)
  • Sieberer, H. (Speaker)
  • Constantin Blöchl (Speaker)
  • Krenn, P. (Speaker)
  • Julia Vetter (Speaker)
  • Ancuela Andosch (Speaker)
  • Daniel Neureiter (Speaker)
  • Dirk Strunk (Speaker)
  • Lisa Pleyer (Speaker)
  • Richard Greil (Speaker)
  • Huber, C. (Speaker)
  • Fritz Aberger (Speaker)
  • Horejs-Höck, J. (Speaker)

Activity: Talk or presentationOral presentationscience to science / art to art

Description

Uncontrolled activation of the NLR family pyrin domain containing 3 (NLRP3) inflammasome has detrimental function in a variety of inflammatory diseases, including also hematopoietic malignancies such as acute myeloid leukemia (AML). However, the contribution of NLRP3 to disease progression and the detailed molecular mechanisms of NLRP3 activation in AML are not fully understood.
Here, we demonstrate that bone marrow-derived mononuclear cells of AML patients display enhanced expression of NLRP3, secrete higher levels of inflammasome-related cytokines IL-1β and IL-18 and that NLRP3 correlates with poor overall survival in patients. To study the function of NLRP3 in AML cells in vitro, we generated NLRP3 deficient AML cells by using CRISPR/Cas9 technology. Surprisingly, NLRP3 deficient AML cells showed reduced cell survival in culture, independent of cell proliferation. We investigated the molecular consequences of NLRP3 deletion by using shotgun proteomics and differential proteomic analysis. Thereby, we identified the eIF2 signaling pathway as a potential molecular target of NLRP3 in AML. Validating our proteomic data, we detected a significant increase of eIF2α phosphorylation upon NLRP3 deletion in AML cells. Consistent with the role of eIF2α phosphorylation as an inducer of cell death, NLRP3 deletion resulted in increased levels of cell apoptosis. Furthermore, we investigated the effects of NLRP3 deletion in vivo by injecting NLRP3 deficient AML cells into NSG-S mice. We monitored leukemia development and tumor cell infiltration and thereby observed a significant reduction in body weight loss and splenomegaly. This was accompanied by decreased tumor cell infiltration into peripheral blood, spleen and bone marrow of these mice. Additionally, we assessed tumor cell homing, cell proliferation and cell survival of cell tracker labelled NLRP3 deficient and control cells after xenograft engraftment. Our results demonstrate, that NLRP3 is required for successful bone marrow homing and survival of AML cells in vivo.
We conclude from this data, that deletion of NLRP3 promotes eIF2α phosphorylation resulting in increased AML cell apoptosis and that NLRP3 is essential to promote AML development and progression in vivo. The NLRP3/eIF2 axis might therefore be a newly discovered signaling hub in AML, that needs to be further investigated for future treatment options.
Period19 Sept 202321 Sept 2023
Event title15th ÖGMBT Annual Meeting: Life Sciences and cutting-edge technologies
Event typeConference
LocationSalzburg, AustriaShow on map
Degree of RecognitionInternational

Fields of Science and Technology Classification 2012

  • 106 Biology