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

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.

Therapeutic potential of targeting mTOR in T-cell acute lymphoblastic leukemia (Review)

“…Afterwards, the leukemia initiating potential in xenografts of the CD7 + /CD1asubset of primary T-ALL samples was found to be superior to other subsets (26). The importance of CD34 as a marker of LIC activity in T-ALL patients has nevertheless been documented by independent groups (27,28). However, it has been shown that also CD34 -/CD7 + T-ALL cells displayed LIC proprieties, although at lower levels than CD34 + cells (28).…”

Targeting Leukemia Stem Cells: Which Pathways Drive Self-Renewal Activity in T-Cell Acute Lymphoblastic Leukemia?

“…In particular, the Notch1 signalling pathway activates runx3 expression, which then represses runx1, a tumour suppressor that positively modulates protein kinase C θ expression 22 [ Figure 1(B)]. Finally, compared with wild-type NOTCH1 pediatric t-all, mutated NOTCH1 pediatric t-all has a higher leukemia-initiating cell frequency within the CD34 compartment 37 .…”

Optimization of Cytostatic Leukemia Therapy in an Advection–Reaction–Diffusion Model

“…We let a targeted cytostatic therapy reduces the regeneration of cancer HC in the bone marrow [12][13][14], following a bounded measurable function u(t, x), defined on the cylinder Q := [0, T ] × . The control function u represents a dose-related targeted cytostatic drug, which takes values in the interval [0, 1], and makes the regeneration rate k 2 of cancer HC at lower rate k 2 u.…”

“…Another example is tipifarnib, which competitively inhibits intracellular signaling of tyrosine kinases in cancer HC [9]. These inhibitors have changed the prognosis of leukemia [12,13], and represent key components to control the regeneration of cancer HC [14]. Nevertheless, a resistance of cancer HC to cytostatic therapies may occur, because of either transporters that detect and eject cytostatic drugs or exposure to increasing concentrations of cytostatic drugs.…”