These results indicate that PRC1.1 plays a key role in restricting excessive transcriptional activation by active NOTCH1, thereby acting as a tumor suppressor in the initiation of T-cell leukemogenesis.
Using loss-of-function approaches, we show that Il7r-deficient, but not wild-type, mouse hematopoietic progenitors transduced with constitutively active Notch1failed to generate leukemia upon transplantation into immunodeficient mice, thus providing formal evidence that IL-7R function is essential for Notch1-induced T-cell leukemogenesis.
Here, using the TEL-JAK2 transgenic (TJ2-Tg) mouse model of T-ALL/LBL, which is driven by constitutive JAK/STAT signaling and characterized by the acquisition of Notch1 mutations, we sought to identify stromal cell alterations associated with thymic leukemogenesis.
Here we identify Hairy and Enhancer of Split 1 (HES1), a transcriptional repressor controlled by NOTCH1, as a critical mediator of NOTCH1-induced leukemogenesis strictly required for tumor cell survival.
These results indicate that Notch1 signaling in HSCs promotes CD8(+) SP T cell development, and that T cell leukemogenesis may require additional oncogenic factors other than Notch1 activation.
Active mutations of Notch1 play pivotal roles during leukemogenesis, but the downstream targets and molecular mechanisms of activated Notch1 signaling have not yet been fully clarified.
In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.
Pharmacologic inhibition of Notch signaling in these cells using γ-secretase inhibitors significantly delayed leukemogenesis in vivo. shRNA targeting of Notch1, as well as c-promoter-binding factor 1 (CBF1) and mastermind-like 1 (MAML1), 2 essential cofactors involved in transcriptional activation of Notch target genes, also significantly delayed or inhibited tumorigenesis in vivo.
Indeed, iron-deficient mice developed Notch1-induced T-ALL substantially more slowly than control mice, further supporting a critical role for iron uptake during leukemogenesis.
In agreement with in vitro studies using human primary effusion lymphoma cell lines, we have found that Notch1 was expressed in the majority of HHV-8-positive primary effusion lymphoma cases, corroborating the notion that Notch1 may have an important role in HHV-8-mediated lymphomagenesis of primary effusion lymphoma.
Together, these studies identify a genetic pathway involving Ikzf1, Kras(G12D), and Notch1 in T lineage leukemogenesis, reveal unexpected diversity in Ras-regulated signaling networks, and define biomarkers of drug responses that may inform treatment strategies.
Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis.
These results suggest that Notch-1 mutations can sometimes be acquired as secondary events in leukemogenesis and must be used cautiously as solitary minimal residual disease markers.
Although NOTCH1 mutation occurs infrequently in mature T-cell leukemia/lymphoma, NOTCH1 may be involved in leukemogenesis associated with various forms of T-cell leukemia/lymphoma rather than only with T-ALL.
AML primary samples show high levels of JAGGED1 expression despite the low NOTCH1 pathway activation, consistent with an autonomous JAGGED1 signaling in myeloid leukemogenesis.
As Notch1 gene is involved in the differentiation and leukemogenesis in lymphoid neoplasm, observations suggest that Notch1 is involved in ATRA-modulated differentiation process in APL.