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

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-1 mut...

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Bibliographic Details
Published in:Clinical cancer research 2007-12, Vol.13 (23), p.6964-6969
Main Authors: MANSOUR, Marc R, DUKE, Veronique, FORONI, Letizia, PATEL, Bella, ALLEN, Christopher G, ANCLIFF, Phil J, GALE, Rosemary E, LINCH, David C
Format: Article
Language:English
Subjects:
Adult
Antineoplastic agents
Biological and medical sciences
Child
Chromosomal Instability
Hematologic and hematopoietic diseases
Humans
Leukemia-Lymphoma, Adult T-Cell - genetics
leukemias and lymphomas
Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis
Medical sciences
minimal residual disease
Mutation
Neoplasm Recurrence, Local - genetics
Neoplasm, Residual
Notch-1
pathogenesis
Pharmacology. Drug treatments
Receptor, Notch1 - genetics
T-cell acute lymphoblastic leukemia
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Summary: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-1 mutations 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-1 mutational 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 ≤10%), 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 secondary T-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.
ISSN:1078-0432
1557-3265
DOI:10.1158/1078-0432.CCR-07-1474