title: NOTCH1 signaling promotes human T-cell acute lymphoblastic leukemia initiating cell regeneration in supportive niches.
abstract: BACKGROUND
  Leukemia initiating cells (LIC) contribute to therapeutic resistance through acquisition of mutations in signaling pathways, such as NOTCH1, that promote self-renewal and survival within supportive niches. Activating mutations in NOTCH1 occur commonly in T cell acute lymphoblastic leukemia (T-ALL) and have been implicated in therapeutic resistance. However, the cell type and context specific consequences of NOTCH1 activation, its role in human LIC regeneration, and sensitivity to NOTCH1 inhibition in hematopoietic microenvironments had not been elucidated.
  
  
  RESULTS
  We established humanized bioluminescent T-ALL LIC mouse models transplanted with pediatric T-ALL samples that were sequenced for NOTCH1 and other common T-ALL mutations. In this study, CD34(+) cells from NOTCH1(Mutated) T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1(Wild-type) CD34(+) cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1(Mutated) CD34(+) fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1(Mutated) T-ALL LIC-engrafted mice and resulted in depletion of CD34(+)CD2(+)CD7(+) cells that harbor serial transplantation capacity.
  
  
  CONCLUSIONS
  These results reveal a functional hierarchy within the LIC population based on NOTCH1 activation, which renders LIC susceptible to targeted NOTCH1 inhibition and highlights the utility of NOTCH1 antibody targeting as a key component of malignant stem cell eradication strategies.
authors: Department of Medicine, Stem Cell Program and Moores Cancer Center, University of California San Diego, La Jolla, California, United States of America.
authors: Wenxue
authors: W
authors: Ma
authors: Alejandro
authors: A
authors: Gutierrez
authors: Daniel J
authors: DJ
authors: Goff
authors: Ifat
authors: I
authors: Geron
authors: Anil
authors: A
authors: Sadarangani
authors: Christina A M
authors: CA
authors: Jamieson
authors: Angela C
authors: AC
authors: Court
authors: Alice Y
authors: AY
authors: Shih
authors: Qingfei
authors: Q
authors: Jiang
authors: Christina C
authors: CC
authors: Wu
authors: Kang
authors: K
authors: Li
authors: Kristen M
authors: KM
authors: Smith
authors: Leslie A
authors: LA
authors: Crews
authors: Neil W
authors: NW
authors: Gibson
authors: Ida
authors: I
authors: Deichaite
authors: Sheldon R
authors: SR
authors: Morris
authors: Ping
authors: P
authors: Wei
authors: Dennis A
authors: DA
authors: Carson
authors: A Thomas
authors: AT
authors: Look
authors: Catriona H M
authors: CH
authors: Jamieson
mesh_terms: D000293:Adolescent; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002648:Child; D002675:Child, Preschool; D006801:Humans; D051379:Mice; D009154:Mutation / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology* / Q000637:transplantation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology*; D051881:Receptor, Notch1 / Q000378:metabolism*; D012038:Regeneration; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects; D055815:Young Adult
chemical_list: D000911:Antibodies, Monoclonal; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1