Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia.
To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.
Sanda
Takaomi
T
Departments of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Li
Xiaoyu
X
Gutierrez
Alejandro
A
Ahn
Yebin
Y
Neuberg
Donna S
DS
O'Neil
Jennifer
J
Strack
Peter R
PR
Winter
Christopher G
CG
Winter
Stuart S
SS
Larson
Richard S
RS
von Boehmer
Harald
H
Look
A Thomas
AT
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020869:Gene Expression Profiling; D016259:Genes, myc; D006801:Humans; D066298:In Vitro Techniques; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D051379:Mice; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics; D015398:Signal Transduction; D013045:Species Specificity
D004791:Enzyme Inhibitors; C497761:NOTCH1 protein, human; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases