Mutations in TP53 and JAK2 are independent prognostic biomarkers in B-cell precursor acute lymphoblastic leukaemia

Abstract

Background:In B-cell precursor acute lymphoblastic leukaemia (B-ALL), the identification of additional genetic alterations associated with poor prognosis is still of importance. We determined the frequency and prognostic impact of somatic mutations in children and adult cases with B-ALL treated with Spanish PETHEMA and SEHOP protocols.Methods:Mutational status of hotspot regions of TP53, JAK2, PAX5, LEF1, CRLF2 and IL7R genes was determined by next-generation deep sequencing in 340 B-ALL patients (211 children and 129 adults). The associations between mutation status and clinicopathological features at the time of diagnosis, treatment outcome and survival were assessed. Univariate and multivariate survival analyses were performed to identify independent prognostic factors associated with overall survival (OS), event-free survival (EFS) and relapse rate (RR).Results:A mutation rate of 12.4% was identified. The frequency of adult mutations was higher (20.2% vs 7.6%, P=0.001). TP53 was the most frequently mutated gene (4.1%), followed by JAK2 (3.8%), CRLF2 (2.9%), PAX5 (2.4%), LEF1 (0.6%) and IL7R (0.3%). All mutations were observed in B-ALL without ETV6-RUNX1 (P=0.047) or BCR-ABL1 fusions (P<0.0001). In children, TP53mut was associated with lower OS (5-year OS: 50% vs 86%, P=0.002) and EFS rates (5-year EFS: 50% vs 78.3%, P=0.009) and higher RR (5-year RR: 33.3% vs 18.6% P=0.037), and was independently associated with higher RR (hazard ratio (HR)=4.5; P=0.04). In adults, TP53mut was associated with a lower OS (5-year OS: 0% vs 43.3%, P=0.019) and a higher RR (5-year RR: 100% vs 61.4%, P=0.029), whereas JAK2mut was associated with a lower EFS (5-year EFS: 0% vs 30.6%, P=0.035) and a higher RR (5-year RR: 100% vs 60.4%, P=0.002). TP53mut was an independent risk factor for shorter OS (HR=2.3; P=0.035) and, together with JAK2mut, also were independent markers of poor prognosis for RR (TP53mut: HR=5.9; P=0.027 and JAK2mut: HR=5.6; P=0.036).Conclusions:TP53mut and JAK2mut are potential biomarkers associated with poor prognosis in B-ALL patients.

Anti‐CD19 chimeric antigen receptor‐modified T‐cell therapy bridging to allogeneic hematopoietic stem cell transplantation for relapsed/refractory B‐cell acute lymphoblastic leukemia: An open‐label pragmatic clinical trial

“…On the other hand, the ten patients with low pre‐infusion MRD and accompanying poor prognostic markers, would have prolonged EFS after receiving allo‐HSCT. The above genes tend to remain or recur, and are indicative of poor prognosis in r/r B‐ALL patients . In this study, two patients suffered from recurrence of high‐risk genes (one BCR‐ABL1, one MLL‐AF4) and subsequent decrease of CAR‐T cells, and then developed CD19‐positive relapse.…”

New Challenges in Targeting Signaling Pathways in Acute Lymphoblastic Leukemia by NGS Approaches: An Update

“…Mutations in genes of this pathway ( JAK1 , JAK2 , JAK3 , IL7R ) have been observed in B-ALL and T-ALL [ 24 , 25 , 49 ]. Mutations in JAK kinases and IL7R cause constitutive activation of the JAK-STAT pathway [ 27 ].…”

“…Mutations in JAK kinases and IL7R cause constitutive activation of the JAK-STAT pathway [ 27 ]. Activating mutations of JAKs genes (primarily JAK2 but also JAK1 and JAK3 ) are also associated with other genetic lesions such as IKZF1 deletion or mutation and CRLF2 - rearrangements ( CRFL2 -r) [ 49 , 50 ]. Similarly, loss-of-function mutations in the SH2B3 gene, which is a negative regulator of JAK2 signaling, have been identified in ALL.…”

Strong expression of p53 protein in bone marrow samples after hematopoietic stem cell transplantation indicates risk of relapse in pediatric acute lymphoblastic leukemia patients

“…4,5 TP53 mutations are rare in pediatric ALLs, yet appear to be more common in subgroups of pediatric ALLs with certain genetic profiles, such as hypodiploidy ALL or N-MYC rearrangements. 6 Mutations of TP53 have been found in 2% of children at diagnosis of ALL, 7 but in 11%-28% after relapse, and are associated with lower OS, lower EFS, and higher RR, 8 indicating involvement in progression to more aggressive disease. 7,[9][10][11][12][13][14] We have previously shown an increased expression of p53 protein in children with myeloid leukemias, who relapse after HSCT.…”