Inflammasome Activation in Myeloid Malignancies-Friend or Foe?

Abstract

Myeloid malignancies including myelodysplastic syndromes, myeloproliferative neoplasms and acute myeloid leukemia are heterogeneous disorders originating from mutated hematopoietic stem and progenitor cells (HSPCs). Genetically, they are very heterogeneous and characterized by uncontrolled proliferation and/or blockage of differentiation of abnormal HSPCs. Recent studies suggest the involvement of inflammasome activation in disease initiation and clonal progression. Inflammasomes are cytosolic innate immune sensors that, upon activation, induce caspase-1 mediated processing of interleukin (IL) -1-cytokine members IL-1β and IL-18, as well as initiation of gasdermin D-dependent pyroptosis. Inflammasome activation leads to a pro-inflammatory microenvironment in the bone marrow, which drives proliferation and may induce clonal selection of mutated HSPCs. However, there are also contradictory data showing that inflammasome activation actually counteracts leukemogenesis. Overall, the beneficial or detrimental effect of inflammasome activation seems to be highly dependent on mutational, environmental, and immunological contexts and an improved understanding is fundamental to advance specific therapeutic targeting strategies. This review summarizes current knowledge about this dichotomous effect of inflammasome activation in myeloid malignancies and provides further perspectives on therapeutic targeting.

Keywords: NLRP3 inflammasome; acute myeloid leukemia and targeting inflammasomes; chronic myeloid leukemia; myelodysplastic syndromes; myeloid malignancies; myeloproliferative neoplasms.

FIGURE 1

Inflammasome configuration and activation. (A) Domain structure of the NLR proteins that form active inflammasomes and non-NLR inflammasome AIM2 and Pyrin (above). Known activators of inflammasome formation (below). (B) Suggested activation scheme for canonical and non-canonical NLRP3 inflammasome formation. In the canonical pathway, NF-κB–activation by TLR ligation in the first step increases transcription and translation of NLRP3 and pro-IL-1β. In the second step, NLRP3 agonists such as MSU crystals or pore forming toxins induce inflammasome formation and thus allow autocleavage and activation of caspase-1. Matured caspase-1 induces cellular activation by cleavage of the cytokines IL-1β and IL-18, and GSDMD mediated pyroptosis. In non-canonical pathway intracellular LPS binds and activates caspase-11. Active form of caspase-11 mediates GSDMD-dependent pyroptosis and further activation of NLRP3 inflammasome.