In addition to NF-?B-mediated survival/proliferation and caspase 8-mediated apoptosis, recent studies demonstrated that tumor necrosis factor-? (TNF hereafter) also induces a RIP1/RIP3-mediated necroptosis (a type of programmed necrosis) in most types of cells. We found that acute monocytic leukemia cells (AMoL hereafter), including subtypes M4 and 5 of acute myeloid leukemia, produce TNF. Compared to normal hematopoietic stem/progenitor cells (HSPCs), AMoL cells are resistant to TNF-induced apoptosis/necroptosis. TNF stimulates the clonogenic growth of AMoL cells at least partially by inducing RIP1/RIP3-mediated differentiation blockage. This pathway also mediates hematopoietic repression of TNF by inducing necroptosis/apoptosis. We propose that TNF represses AMoL cell differentiation by stimulating RIP1/RIP3 signal-dependent SOCS1 (suppressor of cytokine signaling-1) expression. We found that inactivation of TNF-RIP1/RIP3 signaling by a specific inhibitor or genetic deletion induces partial differentiation of AMoL cells which is correlated to the down-regulation of SOCS1 protein. The differentiation of TNF-RIP1/RIP3-inactivated AMoL cells can be further enhanced by interferon (IFN)-? or IFN-?, known inducers of AMoL cell differentiation. Our studies suggest that inhibition of TNF-RIP1/RIP3 might benefit AMoL patients by inducing leukemic cell differentiation while affording protection to normal HSPCs. Inhibiting TNF-RIP1/RIP3 signaling combined with IFN-? or IFN-? might to be a novel treatment approach for AMoL. We want to evaluate the efficacy of such treatment in vivo using murine leukemic models and in vitro using primary AMoL cells. We also intend to study the molecular mechanisms by which the TNF-RIP1/RIP3 signal regulates the level of SOCS1 in AMoL cells.

Public Health Relevance

We found that TNF, acting through the RIP1/RIP3 signal, blocks the differentiation and promotes the growth of acute monocytic leukemia cells. TNF uses the same signal to induce cell death and repress growth of normal hematopoietic cells. Our studies suggested that inhibition of the TNF-RIP1/RIP3 signal could be a novel therapeutic strategy for this type of leukemia, especially if used in combination with other differentiation inducers, such as interferon.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21CA181970-01
Application #
8622508
Study Section
Special Emphasis Panel (ZCA1-SRLB-C (O1))
Program Officer
Mufson, R Allan
Project Start
2014-01-01
Project End
2015-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$197,055
Indirect Cost
$66,555
Name
Loyola University Chicago
Department
Pathology
Type
Schools of Medicine
DUNS #
791277940
City
Maywood
State
IL
Country
United States
Zip Code
60153