The impact of NOTCH1, FBW7 and PTEN mutations on prognosis and downstream signaling in pediatric T-cell acute lymphoblastic leukemia: a report from the Children's Oncology Group

Abstract

We explored the impact of mutations in the NOTCH1, FBW7 and PTEN genes on prognosis and downstream signaling in a well-defined cohort of 47 pediatric T-cell acute lymphoblastic leukemia (T-ALL) patients. In T-ALL lymphoblasts, we identified high frequency mutations in NOTCH1 (n=16), FBW7 (n=5) and PTEN (n=26). NOTCH1 mutations resulted in 1.3-3.3-fold increased transactivation of a HES1 reporter construct over wild-type NOTCH1; mutant FBW7 resulted in further augmentation of reporter gene activity. NOTCH1 and FBW7 mutations were accompanied by increased median transcripts for NOTCH1 target genes (HES1, DELTEX1, cMYC). However, none of these mutations were associated with treatment outcome. Elevated HES1, DELTEX1 and cMYC transcripts were associated with significant increases in transcript levels of several chemotherapy relevant genes, including MDR1, ABCC5, reduced folate carrier, asparagine synthetase, thiopurine methyltranserase, Bcl-2 and dihydrofolate reductase. PTEN transcripts positively correlated with HES1 and cMYC transcript levels. Our results suggest that (1) multiple factors should be considered with attempting to identify molecular-based prognostic factors for pediatric T-ALL, and (2) depending on the NOTCH1 signaling status, modifications in the types or dosing of standard chemotherapy drugs for T-ALL, or combinations of agents capable of targeting NOTCH1, AKT and/or mTOR with standard chemotherapy agents may be warranted.

Regulation of PTEN by CK2 and Notch1 in primary T-cell acute lymphoblastic leukemia: rationale for combined use of CK2- and -secretase inhibitors

“…These observations are in accordance with previous studies demonstrating the importance of MYC as a downstream effector of Notchmediated leukemogenesis, [10][11][12] and with recent evidence that MYC mRNA levels are up-regulated in primary T-ALL cells with NOTCH1 activating mutations. 13 Although NOTCH-mut T-ALL also presented a tendency for higher HES1 levels (median HES1/ABL =-0.954 vs. -1.449) the difference was not statistically significant (P=0.4363; Figure 1B). Importantly, PTEN mRNA levels were significantly decreased in NOTCH-mut primary T-ALL cells (P=0.021; Figure 1C and Table 1).…”

Absence of biallelic TCRγ deletion predicts induction failure and poorer outcomes in childhood T‐cell acute lymphoblastic leukemia

“…35 advances in the molecular typing of leukemia, many new genetic alterations, including mutations and deletions, have been identified. However, their prognostic values have not been widely verified and the results may be controversial [24][25][26][27][28][29][30][31][32][33][34].…”

The relevance of PTEN-AKT in relation to NOTCH1-directed treatment strategies in T-cell acute lymphoblastic leukemia

“…26,27 Restoring PTEN levels in these cell lines decreased cell size and induced apoptosis by suppressing the PI3K-AKT pathway. 28 Studies by others [29][30][31][32][33][34] and our group 21,35 revealed aberrations in the PTEN-PI3K-AKT pathway in approximately 23% of primary samples obtained from pediatric T-ALL patients. With respect to T-ALL subtypes, we have shown that PTEN aberrations are strongly associated with TAL-or LMO-rearranged leukemia in children 21 and the same was observed in adult T-ALL cohorts.…”