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NOTCH1 Mutations in T-Cell Acute Lymphoblastic Leukemia: Prognostic Significance and Implication in Multifactorial Leukemogenesis

Authors' Affiliations: ¹ State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Shanghai Rui Jin Hospital, ² Department of Hematology/Oncology, Shanghai Children's Medical Center and Shanghai Xin Hua Hospital, and ³ Department of Hematology, Shanghai Children's Hospital, Medical School of Shanghai Jiao Tong University, Shanghai, China; and ⁴ Jiangsu Institute of Hematology, Leukemia Research Unit, The First Hospital affiliated to Suzhou University, Medical School of Suzhou University, Suzhou, China

Requests for reprints: Wei-Li Zhao, Shanghai Institute of Hematology, Shanghai Rui-Jin Hospital, Medical School of Shanghai Jiao Tong University, 197 Rui Jin Er Road, Shanghai 200025, China. Phone: 86-21-6437-7859; Fax: 86-21-6474-3206; E-mail: weili_zhao_sih{at}yahoo.com.

Purpose: NOTCH signaling pathway is essential in T-cell development and NOTCH1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To gain insight into its clinical significance, NOTCH1 mutation was investigated in 77 patients with T-ALL.

Experimental Design: Detection of NOTCH1 mutation was done using reverse transcription-PCR amplification and direct sequencing, and thereby compared according to the clinical/biological data of the patients.

Results: Thirty-two mutations were identified in 29 patients (with dual mutations in 3 cases), involving not only the heterodimerization and proline/glutamic acid/serine/threonine domains as previously reported but also the transcription activation and ankyrin repeat domains revealed for the first time. These mutations were significantly associated with elevated WBC count at diagnosis and independently linked to short survival time. Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11.

Conclusion: NOTCH1 mutation is an important prognostic marker in T-ALL and its predictive value could be even further increased if coevaluated with other T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with oncogenic transcriptional factors on T-ALL pathogenesis.

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