Toward aNOTCH1/FBXW7/RAS/PTEN–Based Oncogenetic Risk Classification of Adult T-Cell Acute Lymphoblastic Leukemia: A Group for Research in Adult Acute Lymphoblastic Leukemia Study

Abstract

Purpose The Group for Research in Adult Acute Lymphoblastic Leukemia (GRAALL) recently reported a significantly better outcome in T-cell acute lymphoblastic leukemia (T-ALL) harboring NOTCH1 and/or FBXW7 (N/F) mutations compared with unmutated T-ALL. Despite this, one third of patients with N/F-mutated T-ALL experienced relapse. Patients and Methods In a series of 212 adult T-ALLs included in the multicenter randomized GRAALL-2003 and -2005 trials, we searched for additional N/K-RAS mutations and PTEN defects (mutations and gene deletion). Results N/F mutations were identified in 143 (67%) of 212 patients, and lack of N/F mutation was confirmed to be associated with a poor prognosis. K-RAS, N-RAS, and PTEN mutations/deletions were identified in three (1.6%) of 191, 17 (8.9%) of 191, and 21 (12%) of 175 patients, respectively. The favorable prognostic significance of N/F mutations was restricted to patients without RAS/PTEN abnormalities. These observations led us to propose a new T-ALL oncogenetic classifier defining low-risk patients as those with N/F mutation but no RAS/PTEN mutation (97 of 189 patients; 51%) and all other patients (49%; including 13% with N/F and RAS/PTEN mutations) as high-risk patients. In multivariable analysis, this oncogenetic classifier remained the only significant prognostic covariate (event-free survival: hazard ratio [HR], 3.2; 95% CI, 1.9 to 5.15; P < .001; and overall survival: HR, 3.2; 95% CI, 1.9 to 5.6; P < .001). Conclusion These data demonstrate that the presence of N/F mutations in the absence of RAS or PTEN abnormalities predicts good outcome in almost 50% of adult T-ALL. Conversely, the absence of N/F or presence of RAS/PTEN alterations identifies the remaining cohort of patients with poor prognosis.

Identification of fusion genes and characterization of transcriptome features in T-cell acute lymphoblastic leukemia

“…Currently, the 5-y survival rate of pediatric T-ALL has reached more than 80% (1). In adult T-ALL, while significant therapeutic progress has been made in advanced hematology/oncology centers with a 5-y survival rate of over 60% (2), there are still challenges to improve the clinical prognosis in many cases. A better understanding of T-ALL in an adult group may allow more rational disease stratification and precision therapy.…”

“…On the other hand, fusion genes are also common (20-30% in T-ALL), generating overexpression of mRNAs with ORFs for wild-type protein (such as TAL1 in STIL-TAL1) (9, 10) or transcripts containing fusions between two truncated ORFs such as SET-NUP214 (11). A number of gene abnormalities in pathways regulating differentiation, proliferation, self-renewal, and survival of T-cell precursors are also found in high frequencies, such as mutations of NOTCH1, JAK-STAT, PI3K-AKT, or RAS-MAPK pathway genes and CDKN2A/2B deletions (2,5,(12)(13)(14)(15).…”

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

“…In a French Group for Research in Adult ALL study of T-ALL patients, those with aberrations in RAS and/or PTEN had a significantly worse outcome compared to patients without such mutations. 36 This was not confirmed in the MRC UKALL2003 trial for pediatric T-ALL; RAS and/or PTEN aberrations also did not change the favorable outcome of patients with NOTCH1/FBWX7 mutations. 44 Taken together, these findings suggest that PTEN aberrations may represent a general, poor prognostic factor in T-ALL.…”

“…21 In diagnostic samples from patients with TALLMO, PTEN is frequently inactivated in the absence of NOTCH-activating mutations. 21,32,36,59 Thus, mutations in PTEN and NOTCH1/FBXW7 are frequently independent genetic events and only co-occur in a small number of patients' primary samples. In those patients who harbor both PTEN mutations and NOTCH1/FBXW7 mutations, the NOTCH1 mutations are usually weakly activating mutations.…”

“…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. 36 The vast majority of PTEN aberrations are nonsense mutations in exon 7 (which truncate the Cterminal domain) and deletions that affect nearly the entire locus (Figure 1). Although truncated PTEN proteins that lack the lipid-binding C-terminal domain retain their phosphatase activity, they are highly unstable and are degraded rapidly.…”