3 research outputs found
Regenerating normal B-cell precursors during and after treatment of acute lymphoblastic leukaemia: Implications for monitoring of minimal residual disease
We studied 57 childhood acute lymphoblastic leukaemia (ALL) patients who remained in continuous complete remission after treatment according to the Dutch Childhood Leukaemia Study Group ALL-8 protocols. The patients were monitored at 18 time points during and after treatment [640 bone marrow (BM) and 600 blood samples] by use of cytomorphology and immunophenotyping for the expression of TdT, CD34, CD10 and CD19. Additionally, 60 BM follow-up samples from six patients were subjected to clonality assessment via heteroduplex polymerase chain reaction (PCR) analysis of immunoglobulin VH-JH gene rearrangements. We observed substantial expansions of normal precursor B cells in regenerating BM not only after maintenance therapy but also during treatment. At the end of the 2-week intervals after consolidation and reinduction treatment, B-cell-lineage regeneration was observed in BM with a large fraction of immature CD34+/TdT+ B cells. In contrast, in regenerating BM after cessation of maintenance treatment, the more mature CD19+/CD10+ B cells were significantly increased, but the fraction of immature CD34+/TdT+ B cells
Detection of minimal residual disease identifies differences in treatment response between T-ALL and precursor B-ALL
We performed sensitive polymerase chain reaction-based minimal residual
disease (MRD) analyses on bone marrow samples at 9 follow-up time points
in 71 children with T-lineage acute lymphoblastic leukemia (T-ALL) and
compared the results with the precursor B-lineage ALL (B-ALL) results (n =
210) of our previous study. At the first 5 follow-up time points, the
frequency of MRD-positive patients and the MRD levels were higher in T-ALL
than in precursor-B-ALL, reflecting the more frequent occurrence of
resistant disease in T-ALL. Subsequently, patients were classified
according to their MRD level at time point 1 (TP1), taken at the end of
induction treatment (5 weeks), and at TP2 just before the start of
consolidation treatment (3 months). Patients were considered at low risk
if TP1 and TP2 were MRD negative and at high risk if MRD levels at TP1 and
TP2 were 10(-3) or higher; remaining patients were considered at
intermediate risk. The relative distribution of patients with T-ALL (n =
43) over the MRD-based risk groups differed significantly from that of
precursor B-ALL (n = 109). Twenty-three percent of patients with T-ALL and
46% of patients with precursor B-ALL were classified in the low-risk group
(P =.01) and had a 5-year relapse-free survival (RFS) rate of 98% or
greater. In contrast, 28% of patients with T-ALL were classified in the
MRD-based high-risk group compared to only 11% of patients with precursor
B-ALL (P =.02), and the RFS rates were 0% and 25%, respectively (P =.03).
Not only was the distribution of patients with T-ALL different over the
MRD-based risk groups, the prognostic value of MRD levels at TP1 and TP2
was higher in T-ALL (larger RFS gradient), and consistently higher RFS
rates were found for MRD-negative T-ALL patients at the first 5 follow-up
time points
The significance of PTEN and AKT aberrations in pediatric T-cell acute lymphoblastic leukemia
Background PI3K/AKT pathway mutations are found in T-cell acute lymphoblastic leukemia, but their overall impact and associations with other genetic aberrations is unknown. PTEN mutations have been proposed as secondary mutations that follow NOTCH1-activating mutations and cause cellular resistance to γ-secretase inhibitors. Design and Methods The impact of PTEN, PI3K and AKT aberrations was studied in a genetically well-characterized pediatric T-cell leukemia patient cohort (n=146) treated on DCOG or COALL protocols. Results PTEN and AKT E17K aberrations were detected in 13% and 2% of patients, respectively. Defective PTEN-splicing was identified in incidental cases. Patients without PTEN protein but lacking exon-, splice-, promoter mutations or promoter hypermethylation were present. PTEN/AKTmutations were especially abundant in TAL- or LMO-rearranged leukemia but nearly absent in TLX3-rearranged patients (P=0.03), the opposite to that observed for NOTCH1- activating mutations. Most PTEN/AKT mutant patients either lacked NOTCH1-activating mutations (P=0.006) or had weak NOTCH1-activating mutations (P=0.011), and consequently expressed low intracellular NOTCH1, cMYC and MUSASHI levels. T-cell leukemia patients without PTEN/AKT and NOTCH1-activating mutations fared well, with a cumulative incidence of relapse of only 8% versus 35% for PTEN/AKT and/or NOTCH1-activated patients (P=0.005). Conclusions PI3K/AKT pathway aberrations are present in 18% of pediatric T-cell acute lymphoblastic leukemia patients. Absence of strong NOTCH1-activating mutations in these cases may explain cellular insensitivity to γ-secretase inhibitors