Integrated genomic analyses identify high-risk factors and actionable targets in T-cell acute lymphoblastic leukemia

Abstract

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy often associated with poor outcomes. To identify high-risk factors and potential actionable targets for T-ALL, we perform integrated genomic and transcriptomic analyses on samples from 165 Chinese pediatric and adult T-ALL patients, of whom 85% have outcome information. The genomic mutation landscape of this Chinese cohort is very similar to the Western cohort published previously, except that the rate of NOTCH1 mutations is significant lower in the Chinese T-ALL patients. Among 47 recurrently mutated genes in 7 functional categories, we identify RAS pathway and PTEN mutations as poor survival factors for non-TAL and TAL subtypes, respectively. Mutations in the PI3K pathway are mutually exclusive with mutations in the RAS and NOTCH1 pathways as well as transcription factors. Further analysis demonstrates that approximately 43% of the high-risk patients harbor at least one potential actionable alteration identified in this study, and T-ALLs with RAS pathway mutations are hypersensitive to MEKi in vitro and in vivo. Thus, our integrated genomic analyses not only systematically identify high-risk factors but suggest that these high-risk factors are promising targets for T-ALL therapies.

Analysis of RAS gene mutations in adverse events during first induction chemotherapy in childhood acute lymphoblastic leukemia

“…The RAS mutation rate in children with B-ALL was higher than that in children with T-ALL, which was basically consistent with the report by Wiemels et al ( 24 ). Studies have reported that the RAS pathway can be used as a poor prognostic factor for B-ALL and that T-ALL with RAS pathway mutations are allergic to MEK inhibitor in vitro and in vivo ( 25 ). Huang et al ( 26 ) analyzed bone marrow samples from 368 children newly diagnosed with Philadelphia chromosome-negative acute lymphoblastic leukemia (Ph-ALL), and found that RAS pathway mutation and IKZF1 deletion were independent predictors of poor prognosis.…”

TNFAIP3 mutation is an independent poor overall survival factor for patients with T‐cell acute lymphoblastic leukemia

“…Although pediatric and adult T‐ALL are both heterogeneous diseases caused by accumulation of genetic alterations in progenitor T‐cells, there are differences in the mutation patterns between pediatric and adult patients. 26 , 52 Importantly, exome sequencing has identified recurrent genetic alterations in T‐ALL. For example, NOTCH1 mutations are present in greater than 60% of T‐ALL cases, and activation of oncogenic transcription factors, which often results from rearrangement to the TCR locus, is also a biomarker for T‐ALL.…”

“… 8 , 16 , 22 , 23 , 24 , 25 Whole‐exome sequencing data from 121 T‐ALL patients in the PRJCA002270 dataset, including 96 children, 22 adults, and 3 cases of unknown age, were downloaded from the BioProject database ( https://ngdc.cncb.ac.cn/bioproject/browse/PRJCA002270 ). 26 …”

“…Moreover, RMST was used to evaluate the performance of the Kaplan-Meier curve, and the 3-year RMST for T-ALL patients with and without TNFAIP3 mutation was 14 (95% CI: 6-22) and 26 (95% CI: 22-30) months, respectively (Figure3A). However, TNFAIP3 mutation significantly predicted poor OS in T-ALL patients (HR = 4.63; 95% CI: 1.79-11.96; 3-year OS: 0% vs. 39%; p < 0.001) and a short 3-year RMST [9 (95% CI: 3-14) vs. 23 (95% CI:[19][20][21][22][23][24][25][26][27][28]…”

Blockade of FGF2/FGFR2 partially overcomes bone marrow mesenchymal stromal cells mediated progression of T-cell acute lymphoblastic leukaemia

“…T-cell acute lymphoblastic leukaemia (T-ALL) is a heterogeneous haematological malignancy [ 1 , 2 ]. Leukaemia cells destroy the normal bone marrow (BM) microenvironment, converting it to an abnormal niche [ 3 – 5 ] and the niche components, such as mesenchymal stromal cells (MSCs), in turn confer better survival chances to leukaemia cells, leading to the rapid progression of T-ALL [ 6 , 7 ].…”