Notch-1 mutations are secondary events in some patients with T-cell acute lymphoblastic leukemia.
OBJECTIVE
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.


METHODS
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 < or =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.
Department of Haematology, University College London, UK. m.mansour@ucl.ac.uk
Marc R
MR
Mansour
Veronique
V
Duke
Letizia
L
Foroni
Bella
B
Patel
Christopher G
CG
Allen
Phil J
PJ
Ancliff
Rosemary E
RE
Gale
David C
DC
Linch
D000328:Adult; D002648:Child; D043171:Chromosomal Instability; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics*; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D018365:Neoplasm, Residual; D051881:Receptor, Notch1 / Q000235:genetics*
C497761:NOTCH1 protein, human; D051881:Receptor, Notch1