Journal Article

NOTCH1 Signaling Promotes Human T-Cell Acute Lymphoblastic Leukemia Initiating Cell Regeneration in Supportive Niches

Jamieson, Catriona H. M., Li, Kang, Wei, Ping, Carson, Dennis A., Ma, Wenxue, Sadarangani, Anil, Shih, Alice Y., Jiang, Qingfei, Goff, Daniel J., Court, Angela C., Smith, Kristen M., Crews, Leslie A., Gibson, Neil W., Wu, Christina C., Morris, Sheldon R., Look, A. Thomas, Gutierrez, Alejandro, Geron, Ifat, Deichaite, Ida, Jamieson, Christina A. M.

2012

Overview

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. 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Activation / Acute lymphoblastic leukemia / Acute lymphocytic leukemia / Adolescent / Animal models / Animals / Antibodies, Monoclonal - pharmacology / Apoptosis / Biology / Cancer / CD34 antigen / CD7 antigen / Cell Proliferation - drug effects / Cell self-renewal / Cell survival / Cell Survival - drug effects / Child / Child, Preschool / Engraftment / Health aspects / Humans / Inhibition / Laboratories / Leukemia / Lymphatic leukemia / Lymphocytes T / Medical prognosis / Medicine / Mice / Microenvironments / Monoclonal antibodies / Mutation / Mutation - genetics / Neoplasm Transplantation / Neoplastic Stem Cells - drug effects / Neoplastic Stem Cells - pathology / Neoplastic Stem Cells - transplantation / Notch sensitivity / Notch1 protein / Oncology / Pathogenesis / Pediatrics / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - genetics / Precursor T-Cell Lymphoblastic Leukemia-Lymphoma - pathology / R&D / Receptor, Notch1 - metabolism / Regeneration / Research & development / Signal Transduction - drug effects / Signaling / Stem Cell Niche - drug effects / Stem cell transplantation / Stem cells / Survival / T cells / Transplantation / Young Adult