Notch-1 Mutations Are Secondary Events in Some Patients with T-Cell Acute Lymphoblastic Leukemia

Abstract

Purpose: Activating Notch-1 mutations are frequent in T-cell acute lymphoblastic leukemia (T-ALL), occurring in >50% of patients. In murine models of T-ALL, Notch-1 activation can both directly initiate leukemia and cooperate secondarily to other primary events.Whether acquisition of Notch-1mutations is an early initiating event or a secondary event in the pathogenesis of human T-ALL is unclear. Experimental Design: We used denaturing high-performance liquid chromatography, sequencing, and fragment analysis to analyze Notch-1mutational status and mutant level in 62 patients at presentation as well as 16 matched presentation-relapse samples. Results: We detected Notch-1 mutations in 47 patients (76%). Seven of these were low-level mutations (quantified at V10%), despite high blast counts, suggesting that they were acquired as a secondary event in a subclone. Of 16 matched presentation-relapse samples studied, 7 were wild-type at both presentation and relapse. Five of nine mutant-positive patients at presentation relapsed with the same mutation(s) at the same high level. Four patients had evidence of a change in mutant at relapse. One lost a PEST mutation and became wild-type. Two others lost mutations at relapse but acquired different mutations, despite unchanged T-cell receptor rearrangements, suggesting that the latter event predated the acquisition of the Notch-1 mutation. One relapsed with a secondaryT-cell leukemia and different Notch mutation. Conclusions: 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.

Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients

“…In rodents, Notch1 mutation can directly induce leukemia but also can participate as a secondary collaborator (22,23). Although prenatal NOTCH1 mutation can also act as an initiating factor in human T-ALL, there is good evidence to support this as a secondary event, therefore suggesting that the temporal sequence of genetic lesions is less important than the combinatorial effect (24,25). Here, it appears likely that an activating mutation in the HD-N domain of NOTCH1 is indeed a secondary event following upregulated expression of LMO2, in accordance with mouse models of T-ALL induced by constitutive LMO2 expression (16).…”

The role of the PTEN/AKT Pathway in NOTCH1-induced leukemia

“…21 Activating mutations in NOTCH1 result in ligand independent activation of the receptor or increased ICN1 protein stability in over 50% of T-ALLs. [21][22][23][24][25] Importantly, small molecule inhibitors of the γ-secretase complex (GSIs) effectively abrogate the function of the receptor encoded by these oncogenic NOTCH1 alleles, making NOTCH1 a promising therapeutic target for the treatment of T-ALL. Initial studies treating human T-ALL cell lines harboring activating mutations in NOTCH1 with GSIs demonstrated that inhibition of NOTCH signaling induces cell cycle arrest.…”

Stage-specific Arf tumor suppression in Notch1-induced T-cell acute lymphoblastic leukemia

“…7 Although leukemogenesis is independent of the pre-TCR, per se, ICN1 overexpression cannot induce leukemia in cells that lack pre-TCR signaling, implying that malignant transformation occurs after pre-TCR signaling but before completion of ␣ chain rearrangement. [7][8][9] Although the extent to which NOTCH1 mutations represent founding oncogenic events in T-ALLs has been debated, 10,11 robust mouse models of T-ALL driven by activated Notch1 implicate this pathway as an appealing target for therapeutic intervention. 4,5,[11][12][13] Occurring more frequently than mutation of NOTCH1, deletion of the CDKN2A (hereafter INK4A-ARF) locus, which encodes 2 functionally distinct but closely chromosomally linked tumor suppressors, p16 INK4A and p14 ARF (p19 Arf in the mouse), affects more than 70% of T-ALL cases.…”