Abstract
BackgroundLeukemia 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.Methodology and Principal FindingsWe 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 NOTCH1Mutated T-ALL samples had higher leukemic engraftment and serial transplantation capacity than NOTCH1Wild-type CD34+ cells in hematopoietic niches, suggesting that self-renewing LIC were enriched within the NOTCH1Mutated CD34+ fraction. Humanized NOTCH1 monoclonal antibody treatment reduced LIC survival and self-renewal in NOTCH1Mutated T-ALL LIC-engrafted mice and resulted in depletion of CD34+CD2+CD7+ cells that harbor serial transplantation capacity.ConclusionsThese 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.
Highlights
Seminal research suggests that leukemia relapse occurs because standard chemotherapy fails to eradicate self-renewing leukemia initiating cells (LIC) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]
These results reveal a functional hierarchy within the Leukemia initiating cells (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
While the LIC population was found to be an essential driver of therapeutic resistance and relapse, the NOTCH1 mutational status of the LIC population was not established; the cell surface phenotype changed during the prolonged engraftment period and niche dependence of LIC maintenance, which could contribute to relapse, was not elucidated
Summary
Seminal research suggests that leukemia relapse occurs because standard chemotherapy fails to eradicate self-renewing leukemia initiating cells (LIC) [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15]. ABL1 ALL harboring a predominant clone at diagnosis have increased rates of early relapse thereby linking LIC clonal dominance with a poorer prognosis [18] In another leukemia subtype that is prone to early relapse [19], pediatric T cell acute lymphoblastic leukemia (T-ALL), serially transplantable LIC were found to be enriched in CD34+CD42 and CD34+CD72 fractions of newly diagnosed patient samples [12]. The high propensity for T-ALL relapse underscores the need for LIC characterization based on functional molecular drivers of survival and self-renewal and spatiotemporal tracking of niche dependence in bioluminescent serial xenotransplantation models Together these compelling studies provided the impetus for investigating the potential LIC propagating capacity of NOTCH1 mutations, implicated in T-ALL therapeutic resistance [10] and sensitivity to targeted NOTCH1 inhibition within selective niches. 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
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