Activating NOTCH1 Mutations Are Associated with Good Treatment Response in Childhood T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1444-1444
Author(s):  
Stephen Breit ◽  
Martin Stanulla ◽  
Thomas Flohr ◽  
Martin Schrappe ◽  
Wolf-Dieter Ludwig ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Confidence Interval ◽  
Treatment Response ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact ◽  
Notch1 Mutations

Abstract T-cell acute lymphoblastic leukemia (T-ALL) accounts for 10–15 % of pediatric ALL. Very rare cases of T-ALL (< 1 %) harbor the chromosomal translocation t(7;9) that involves NOTCH1, a gene encoding a single-pass, heterodimeric transmembrane receptor. NOTCH1 has an essential function in early intrathymic T-cell development. Recently, it has been demonstrated that more than 50 % of childhood T-ALLs carry activating mutations within the NOTCH1 gene (Weng et al., Science 2004). In the present study, we systematically analyzed the impact of activating NOTCH1 mutations on treatment response in 108 pediatric T-ALLs, registered in the ongoing ALL-BFM 2000 trial. In 56 cases (51.8%) activating NOTCH1 mutations were identified, located either in the heterodimerization (38/56 mutations; 65.5%), in the PEST (10/56; 17.9%) or in both domains (8/56; 14.3%). The presence of activating NOTCH1 mutations was significantly correlated with good prednisolone (p = 0.001, c2 or Fisher’s exact test) and MRD response (p = 0.002). T-ALLs with NOTCH1 mutations were 3.7 times more likely to show a good prednisolone response (95% confidence interval = 1.64–8.33; p = 0.002) and 4.8 times more likely to show a favorable MRD response (95% confidence interval = 2.04–11.11; p = 0.0003) when compared to patients with wild type NOTCH1. Patients with mutated NOTCH1 were thus underrepresented in the high risk group of the ALL-BFM 2000 protocol. This influence of NOTCH1 mutational status on risk stratification was independent from other commonly used criteria, like age and initial white blood cell count (WBC) at the time of diagnosis. Considering the impact of NOTCH1 mutations on long term prognosis, we analyzed those 49 patients of this cohort with a median follow-up of > 4 years. Eight patients relapsed within this follow-up period, 2 patients with mutated and 6 with wild type NOTCH1. With this small number of relapses, this trend towards a favorable influence of activating NOTCH1 mutations on EFS did not reach statistical significance. In conclusion, T-ALLs with NOTCH1 mutations are demonstrated to be more sensitive than those without to the ALL-BFM 2000 treatment strategy and may show a lower rate of relapse.

scholarly journals Overexpression of wild type IL-7Rα promotes T-cell acute lymphoblastic leukemia/lymphoma

Blood ◽  
2021 ◽  
Author(s):  
Ana Patricia Silva ◽  
Afonso R.M. Almeida ◽  
Ana Cachucho ◽  
João L Neto ◽  
Sofie Demeyer ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Mrna Levels ◽  
Wild Type ◽  
Transcriptional Signature ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Signaling Activation ◽  
Mutational Activation ◽  
The Impact

Tight regulation of IL-7Rα expression is essential for normal T-cell development. IL-7Rα gain-of-function mutations are known drivers of T-cell acute lymphoblastic leukemia (T-ALL). Although a subset of T-ALL patients display very high IL7R mRNA levels and cases with IL7R gains have been reported, the impact of IL-7Rα overexpression, rather than mutational activation, on leukemogenesis remains unclear. Here, we show that overexpression of IL-7Rα in tetracycline-inducible Il7r transgenic and Rosa26 IL7R knock-in mice drives potential thymocyte self-renewal, and thymus hyperplasia due to increased proliferation of T-cell precursors, which subsequently infiltrate lymph nodes, spleen and bone marrow, ultimately leading to fatal leukemia. The tumors mimic key features of human T-ALL, including heterogeneity in immunophenotype and genetic subtype between cases, frequent hyperactivation of PI3K/Akt pathway that is paralleled by downregulation of p27Kip1 and upregulation of Bcl-2, and gene expression signatures evidencing JAK/STAT, PI3K/Akt/mTOR and Notch signaling activation. Notably, we also find that established tumors may no longer require high levels of IL-7R expression upon secondary transplantation and can progress in the absence of IL-7, but remain sensitive to inhibitors of IL-7R-mediated signaling Ruxolitinib (Jak1), AZD1208 (Pim), Dactolisib (PI3K/mTOR), Palbociclib (Cdk4/6), and Venetoclax (Bcl-2). The relevance of these findings for human disease are highlighted by the fact that T-ALL patient samples with high wild type IL7R expression display a transcriptional signature resembling that from IL-7-stimulated pro-T cells and, critically, from IL7R mutant T-ALL cases. Overall, our studies demonstrate that high expression of IL-7Rα can promote T-cell tumorigenesis even in the absence of IL-7Rα mutational activation.

scholarly journals A Feasibility and Safety Study of Non-Viral Genome Targeting Anti-CD19 CAR-T in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 19-20
Author(s):  
Yi Wang ◽  
Hui Wang ◽  
Ying Gao ◽  
Ding Zhang ◽  
Yan Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase I ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: It has been made great clinical progresses in hematological malignancies by chimeric antigen receptor (CAR) T cell therapy which utilizes virus vector for manufacture. However, there're still issues unresolved, for instance, sophisticated virus production process, deadly Cytokine Release Syndrome (CRS) side-effect, and high recurrence rate, which probably limit the availability of CAR-T therapy. Non-viral Genome Targeting CAR-T (nvGT CAR-T) may provide a feasible solution to those unmet needs mentioned above. We used CRISPR-Cas9 and non-viral vector to insert anti-CD19 CAR DNA to a specific genome locus in human T cells, which in theory, produces more moderate CAR-T cells compared with conventional CAR-T cells. The efficacy of anti-CD19 nvGT CAR-T cells had been demonstrated in our previous pre-clinical studies, and in this Phase I clinical trial (ChiCTR2000031942), its safety and efficacy in relapsed/refractory B-Cell Acute Lymphoblastic Leukemia (r/r B-ALL) patients were explored. Objective: The primary objective of this Phase I trial is to assess safety, including evaluation of adverse events (AEs) and AEs of special interest, such as CRS and neurotoxicity. Secondary objective is to evaluate efficacy as measured by the ratio of complete remission (CR). Method: Peripheral blood mononuclear cells were collected from patients or allogeneic donors, then CD3+ T cells were selected and modified by nvGT vector to produce anti-CD19 CAR-T, then administrated to patients with r/r B-ALL. Up to July 2020, twelve patients with r/r B-ALL had been enrolled in this study and 8 patients completed their treatments and entered follow-up period. For 8 patients with follow-up data, the median age was 33 years (range, 13 to 61), and the median number of previous regimens was 5 (range, 2 to 11). The median baseline percentage of bone marrow (BM) blast is 72% (range, 24.5% to 99%). Among those subjects, 2 patients once have been conducted autologous or allogeneic hematopoietic stem cell transplantation (Auto-HSCT or Allo-HSCT), and 2 patients experienced serious infection before CAR-T infusion. No patient has been treated by any other CAR-T therapy before enrollment. Baseline characteristics refer to Table 1. Administering a lymphodepleting chemotherapy regimen of cyclophosphamide 450-750 mg/m2 intravenously and fludarabine 25-45 mg/m2 intravenously on the fifth, fourth, and third day before infusion of anti-CD19 nvGT CAR-T, all patients received an infusion at dose of 0.55-8.21×106/kg (Table 1). Result: Until day 30 post CAR-T cell infusion, 8/8 (100%) cases achieved CR and 7/8 (87.5%) had minimal residual disease (MRD)-negative CR (Table 1). Anti-bacterial and anti-fungal were performed in patients SC-3, SC-4 and SC-5 after CAR-T cell infusion, which seems no influence on efficacy. Patient SC-7 was diagnosed as T-cell Acute Lymphoblastic Leukemia before Allo-HSCT but with recent recurrence of B-ALL, which was MRD-negative CR on day 21 post nvGT CAR-T therapy. Up to July 2020, all cases remain CR status. CRS occurred in all patients (100%) receiving anti-CD19 nvGT CAR-T cell, including 1 patient (12.5%) with grade 3 (Lee grading system1) CRS, two (25%) with grade 2 CRS, and 5 (62.5%) with grade 1 CRS. There were no cases of grade 4 or higher CRS (Table 1). The median time to onset CRS was 9 days (range, 1 to 12 days) and the median duration of CRS was 6 days (range, 2 to 9 days). None developed neurotoxicity. No fatal or life-threatening reactions happened and no Tocilizumab and Corticosteroids administered following CAR-T treatment. Data including body temperature (Figure 1), CAR-positive T cell percentage (Figure 2), Interleukin-6 (IL-6) and Interleukin-8 (IL-8) (Figure 3 and 4), C-reactive Protein (CRP) (Figure 5), Lactate Dehydrogenase (LDH) (Figure 6), and Procalcitonin (PCT) (Figure 7), are in accordance with the trend of CRS. Conclusion: This Phase I clinical trial primarily validates the efficacy of this novel CAR-T therapy, however, it still needs time to prove its durability. Surprisingly, we find that nvGT CAR-T therapy is seemingly superior than viral CAR-T therapy in terms of safety. All subjects which are high-risk patients with high tumor burden had low grade CRS, even a few patients sent home for observation post infusion with limited time of in-patient care. Furthermore, patients could tolerate a higher dose without severe adverse events, which probably bring a better dose-related efficacy. Disclosures No relevant conflicts of interest to declare.

Role of cranial radiotherapy for childhood T-cell acute lymphoblastic leukemia with high WBC count and good response to prednisone. Associazione Italiana Ematologia Oncologia Pediatrica and the Berlin-Frankfurt-Münster groups.

1997 ◽  
Vol 15 (8) ◽  
pp. 2786-2791 ◽  
Author(s):  
V Conter ◽  
M Schrappe ◽  
M Aricó ◽  
A Reiter ◽  
C Rizzari ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Group Versus ◽  
Rank Test ◽  
Intrathecal Methotrexate ◽  
Intrathecal Therapy ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Wbc Count ◽  
The Impact

PURPOSE The ALL-BFM 90 and AIEOP-ALL 91 studies share the same treatment backbone and have 5-year event-free survival (EFS) rates close to 75%. This study evaluated the impact of differing presymptomatic CNS therapies in T-cell acute lymphoblastic leukemia (T-ALL) patients with a good response to prednisone (PGR) according to WBC count and Berlin-Frankfurt-Münster (BFM) risk factor (RF). PATIENTS A total of 192 patients (141 boys; median age, 7.5 years) with T-ALL, PGR, RF less than 1.7, and no CNS leukemia diagnosed between 1990 and 1995 were enrolled onto the ALL-BFM 90 (n = 123) or AIEOP-ALL 91 (n = 69) study. Presymptomatic CNS therapy consisted of cranial radiation (CRT) and intrathecal methotrexate (I.T. MTX) (11 doses) in the BFM study and of extended triple intrathecal therapy (T.I.T.) (17 doses) in the Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) study. Patients were divided into a low-WBC group (WBC count < 100,000/microL) and a high-WBC group (WBC count > 100,000/microL). EFS was compared using the log-rank test. RESULTS For patients treated with CRT and I.T. MTX (BFM group), the 3-year EFS rate was 89.8% (SE = 3.5) for 99 patients in the low-WBC group versus 81.9% (SE = 8.2) in the high-WBC group (difference not significant). Conversely, for patients treated with T.I.T. alone (AIEOP group), the EFS rate was 80.6% (SE = 5.6) in 55 patients with a low WBC count versus 17.9% (SE = 11.0) in 14 patients with a high WBC count (P < .001). CONCLUSION These data suggest that CRT may not be necessary in PGR T-ALL patients with a WBC count less than 100,000/microL; on the contrary, in patients with a high count, extended T.I.T. may be inferior to CRT and I.T. MTX.

Clinical Significance of Alterations of the NOTCH1, FLT3 and p53 Genes in Pediatric T-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4434-4434
Author(s):  
Myoung-ja Park ◽  
Tomohiko Taki ◽  
Akira Shimada ◽  
Manabu Sotomatsu ◽  
Ryoji Hanada ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Missense Mutations ◽  
Nonsense Mutations ◽  
Poor Prognostic Factor ◽  
Cell Acute Lymphoblastic Leukemia ◽  
P53 Genes ◽  
Notch1 Mutations

Abstract Activating mutations of the NOTCH1 gene have been reported in about 50% of T cell acute lymphoblastic leukemia (T-ALL). We performed mutation analysis of the NOTCH1, FLT3 and p53 genes by polymerase chain reaction followed by direct sequence. Mutations of the NOTCH1 were identified in 24 (30%) of 80 fresh samples and 10 (71.4%) of 14 T-ALL cell lines. Six missense mutations and 2 insertion in HD domain, 2 nonsense mutations and 6 insertions in PEST domains were found in 14 cell lines. Eight missense mutations, 9 insertions and one deletion in HD domains, 5 missense mutations, 3 nonsense mutations and 3 deletions in PEST domain were found in 80 fresh samples. The incidence of the NOTCH1 mutations is less frequent than that of previous reports. We observed about 95% of single nucleotide polymorphisms (5097 C/T) in HD domain, which is more frequent than 30% of previous report, possibly due to the racial difference. FLT3 internal tandem duplication, which is known as the poor prognostic factor in acute myeloid leukemia, were not identified in any T-ALL cell lines or fresh samples. Mutations of the p53 gene were found in 5 of 8 cell lines and 5 of 50 fresh samples. Mutations of both NOTCH1 and p53 genes were identified 3 of 8 cell lines and one of 50 fresh samples. In our study NOTCH1 mutations were not significantly associated with high WBC count and prognosis. Further studies are needed to find the association between novel genes and clinical features of pediatric T-ALL.

Analysis of Clonal T-Cell Receptor Gamma Gene Rearrangements, NOTCH1, FBW7 and PTEN Mutations in Paired Pediatric T-Cell Acute Lymphoblastic Leukemia Samples at Diagnosis and Relapse Reveals Evidence of Relapse in New Leukemic Clones.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1488-1488
Author(s):  
Qing Chen ◽  
Amanda Larson Gedman ◽  
Larry H. Matherly ◽  
Jeffrey W. Taub
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tumor Suppressor ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Gene Rearrangements ◽  
Pten Mutation ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Mutations

Abstract Relapse following remission induction chemotherapy remains the major challenge in the successful treatment of childhood T cell acute lymphoblastic leukemia (T-ALL). Relapse often results from the outgrowth of residual leukemia cells that are present below the limit of detection or involves a new therapy-related secondary leukemia. Individualization of treatment might improve the outcome and long-term quality of life for T-ALL patients. Molecular genetic markers represent clinically useful factors which predict responses to therapy. T-cell receptor gamma (TCRG) gene rearrangements occur in more than 90% of T-ALL and provide markers of lymphoblast clonality. Determining rearrangements in the TCRG could be critical to the diagnosis and treatment of T-ALL in children and adults. Mutations in the NOTCH1, FBW7, and PTEN genes have been identified at high frequencies in pediatric T-ALL cases. Activating NOTCH1 mutations have been found in more than 50% of ALL patients, resulting in constitutive NOTCH1 signalling, whereas PTEN mutations are inactivating, resulting in increased PI3K/AKT signalling. FBW7 has been identified as an important tumor suppressor. Several studies reported that frequent mutations in the substrate binding domain (e.g. Arg465, Arg479, Arg505) for FBW7 in T-ALL cell lines and primary T-ALL specimens result in sustained NOTCH1 levels and downstream signalling and gamma secretase inhibitor resistance, suggesting an alternate mechanism for NOTCH1 deregulation. To investigate the mechanism of T-ALL relapse, we analyzed the TCRG gene rearrangements and mutational status of the NOTCH1, FBW7, and PTEN genes by comparing sequences in paired diagnostic and relapsed T-ALL samples from 11 children to evaluate their stabilities throughout disease progression and association with treatment failure. The age distribution of 11 patients ranged from four years to fifteen years. Original TCRG sequence (a measure of leukemia clonality) was fully preserved at relapse in 3 (27.3%) patients. Clonal evolution was identified in 8 (72.7%) patients, reflected in changes in TCRG sequence. In 3 patients at diagnosis, NOTCH1 mutations were detected. At relapse, the major leukemia clones exhibited different NOTCH1 mutations. For another patient, a NOTCH1 mutation was detected at relapse but not at diagnosis. No FBW7 mutations were detected either at diagnosis or relapse. In 5 patients at diagnosis, PTEN mutations were detected and at relapse, 2 preserved the same mutation and 2 lost their mutations, while the additional sample harbored a different PTEN mutation. Our comparative sequence analysis of pediatric T-ALL samples provided detailed insight in the stabilities and changes of TCRG rearrangements and NOTCH1, FBW7 and PTEN mutation status during disease development. Re-emergence of the initial ALL clone or the occurrence of a secondary ALL clone may be clinically important to guide subsequent therapy. Collectively, our results suggest that for the majority of cases, relapse is associated with appearance of a new leukemic clone. For a subset of these cases, this is accompanied by a distinct subset of NOTCH1 mutations and, to a lesser extent, PTEN mutations. FBW7 mutations are rare. Better understanding of the changes in oncogenes and tumor suppressor genes with progression of T-ALL may identify new targets for therapy and facilitate the design of individualized therapy for this disease. Further study is needed to determine whether the newly identified relapse ALL clones were present at diagnosis as minor subclinical populations.

High Mir-221 Expression Is Associated with Poorer Treatment Outcome of Patients with T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1439-1439 ◽  
Author(s):  
Hamilton L. Gimenes-Teixeira ◽  
Guilherme A. dos Santos ◽  
Dalila L. Zanette ◽  
Priscila S Scheucher ◽  
Luciana Correa Oliveira de Oliveira ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mirna Expression ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Cell Counts ◽  
Cell Acute Lymphoblastic Leukemia ◽  
The Impact

Abstract Abstract 1439 T-cell acute lymphoblastic leukemia (T-ALL) is a malignancy of immature T cells that accounts about 15% of pediatric and 25% of adult ALL cases. In the last years, several clinical and laboratory features have been described as prognostic markers; nevertheless, with intensification of therapy most of them have lost their predictive value. MicroRNA (miRNA) expression analysis has proved to be an useful tool for identifying specific subsets of cancer patients with relevant cytogenetic, laboratorial and clinical features. The aim of the present study was to determine if miRNAs may be useful markers in T-ALL. First, we performed a supervised analysis comparing the miRNA expression profile of T-ALL blasts from 36 T-ALL/CD56− and 12 T-ALL/CD56+. We selected CD56 as prognostic marker based on our previous report showing that the disease-free survival (DFS) of T-ALL/CD56+ patients was of 28.5 months compared to 69.8 in the CD56− group. Also patients tended to be older and to present normal platelet counts in the T-LLA/CD56+ group. We used the Taqman MicroRNA Assay Human Panel (Applied Biosystems) to perform a screening of 164 knowledge mature miRNA sequences using specific primers and probes according to manufacturer instructions. Total RNA input was normalized based on the geometric means of Ct values obtained from four endogenous RNAs. All reactions were run in duplicate and a coefficient of variation greater than 5% was used as an exclusion factor (seven miRNAs were excluded). The fold change was calculated using comparative 2−δCt method. We have identified a set of 14 miRNAs differentially expressed, of which miR-374 and miR-221 best distinguished T-ALL/CD56+ from T-ALL/CD56− blasts. Based on this profile, we selected miR-221 and miR-374 as potential markers and quantified their expression in the same samples using RQ-PCR. Patients were stratified as high and low expression using the median value as cut off. We detected a significant association between the miR-221 high expression and poorer treatment outcome. On the contrary, miR-374 expression levels were not associated with treatment outcome. We evaluate the impact of age, white blood cell counts, CD56 and miR221 expression on overall survival (OS). Age and miR-221 were the only ones found to be significant. The estimate 5-year OS (mean and confidence interval 95%) was of 67.0 ± 10.3% in the group of patients expressing miR-221 below the cut-off value, whereas this value was of 28.5 ± 14.5% in the alternative group. Even among T-ALL/CD56− patients, the higher expression of miR-221 was significantly associated with poorer outcome. Our data suggest that miR-221 play an important role in T-ALL and its regulation may represent a potential therapeutic intervention. Disclosures: No relevant conflicts of interest to declare.

TYK2-STAT1 Pathway Positively Regulates BCL2 Gene Expression in T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1470-1470
Author(s):  
Takaomi Sanda ◽  
Jeffrey W Tyner ◽  
Alejandro Gutierrez ◽  
Vu N Ngo ◽  
Jason M Glover ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Protein Expression ◽  
Cell Lines ◽  
Lymphoblastic Leukemia ◽  
Wild Type ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Bcl2 Protein ◽  
Bcl2 Expression

Abstract Abstract 1470 To discover oncogenic pathways that are characteristically deregulated in T-cell acute lymphoblastic leukemia (T-ALL), we performed RNA interference screens both in T-ALL cell lines and primary specimens. We found that the JAK tyrosine kinase family member, TYK2, and its downstream effector, STAT1, are each required for the survival of T-ALL cells. To identify the effector molecules downstream of the TYK2-STAT1 pathway in T-ALL, we analyzed global gene expression profiles in TYK2-dependent T-ALL cell lines after silencing of TYK2 or STAT1. As expected, gene set enrichment analysis revealed that genes downregulated by TYK2 knockdown were generally also downregulated by knockdown of STAT1. Importantly, we found that expression of the anti-apoptotic gene BCL2 was significantly downregulated after silencing of both TYK2 and STAT1. Analysis by quantitative PCR of additional T-ALL cell lines revealed that silencing of TYK2 resulted in significant reductions of BCL2 mRNA expression in multiple TYK2-dependent cell lines. Expression of the wild-type but not the kinase-dead TYK2 protein was sufficient to rescue BCL2 protein expression and to prevent apoptosis after knockdown of endogenous TYK2, indicating that the tyrosine kinase activity of TYK2 is required for BCL2 upregulation. Similarly, expression of the shRNA-resistant wild-type STAT1A protein partially rescued BCL2 protein expression and prevented apoptosis, while a variant of STAT1A (Y701F) that is incapable of becoming phosphorylated on a requisite tyrosine residue did not rescue BCL2 levels. Taken together, our findings indicate that aberrant activation of a TYK2-STAT1 pathway upregulates BCL2 expression in T-ALL cells, and that the T-ALL cells develop pathway dependence, in that they require these sustained high levels BCL2 expression for survival. Disclosures: No relevant conflicts of interest to declare.

Impactof NOTCH1, FBXW7 and SETD2 Mutations On Early Treatment Response In Childhood T-Cell Acute Lymphoblastic Leukemia：A China Children’s Leukemia Group Study

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4937-4937
Author(s):  
Wei Wei ◽  
Xiaojuan Chen ◽  
Yao Zou ◽  
Lixian Chang ◽  
Zhu Xiaofan
Keyword(s):  
T Cell ◽  
High Risk ◽  
Treatment Response ◽  
Lymphoblastic Leukemia ◽  
High Risk Group ◽  
Missense Mutations ◽  
Early Treatment Response ◽  
Notch1 Mutations

Abstract T-cell lymphoblastic leukemia (T-ALL) is an aggressive malignancy accounting for about 15% of newly diagnosed acute lymphoblastic leukemia (ALL) in children. Although the prognosis has been improved by intensified therapies, the outcome of high risk patients is still not optimistic. Activating NOTCH1 and/or FBXW7 mutations have been reported to be the leading genetic abnormality in T-ALL with good prognosis but few studies about the role of NOTCH1 and FBXW7 in T-ALL were conducted in China and their mutation distributions and clinical prognosis are still unclear. On the other hand, loss of function mutations of SETD2, a histone methyltransferase specific for trimethylation of histone H3 on Lys36 (H3K36me3), has been found in renal cell carcinoma, gliomas and early T cell precursor ALL (ETP-ALL). SETD2 is a potential tumor suppressor gene and may play a deleterious role in human cancer. We attempted to investigate the role of these mutations in Chinese T-ALL children. Thirty-seven bone marrow samples from childhood patients with newly diagnosed T-ALL (26 boys and 11 girls; age＜14 years) enrolled into the China Children’s Leukemia Group (CCLG) ALL-2008 trail from September 2010 to December 2012 were analyzed for SETD2, NOTCH1, FBXW7 mutations. All exons of SETD2, exons 25-28, 34 of NOTCH1 and exons 5, 7-12 of FBXW7, including intron-exon boundaries, were sequenced by Sanger method. NOTCH1 mutations were observed in 43.2% (n=16) of the T-ALL patients. Thirteen missense mutations were found in HD-N domain, HD-C domain and TAD domain of NOTCH1 while only frameshift insertions and deletions were identified in PEST domain. Besides missense mutations, five inframe insertions were also observed in HD-N domain of NOTCH1. We only found one FBXW7 synonymous mutation in our patients, which was extremely low compared with that in other studies. SETD2 somatic mutations were found in 8.1% (n=3, one female and two males) of 37 T-ALL patients. Of the three patients, two patients had truncated SETD2 protein because of nonsense mutation (c.6229 C＞T) and frameshift insertion (c.7516_7517insTTATA) respectively. Both SETD2 and NOTCH1 mutations were found in one patient. In our study, no significant relationships between NOTCH1 status and age, sex, mediastinal or Central Nervous System (CNS) involvement, immunophenotype and cytogenetics were observed. However, White Blood Cell (WBC) count at diagnosis in patients without NOTCH1 mutation were much higher (221×109/L vs 76.95×109/L, P=0.015). Patients with NOTCH1 mutations had a better early treatment response: higher prednisone good response rate (81.2% vs 47.6%, p=0.048), higher incidence of bone marrow M1 status (blast cell＜5%) on day 15 (73.3% vs 33.3%, p=0.04), and higher rate of favorable minimal residual disease (MRD) level on day 88 (100% vs 59.9%, p=0.012). In contrast, patients without NOTCH1 mutations were more likely to fall into the high risk group (71.4% vs 21.4%, p= 0.006) according to our treatment protocol. After a median follow-up of 11 months, 1 patient did not reach complete remission (CR), 2 patients died during induction and 2 patients relapsed in 6 months. Patients who suffered relapse and induction failure are all in the NOTCH1 wild type group. SETD2 mutations seemed to have no relationship to sex, age, WBC, cytogenetics, CNS and mediastinal involvement. In contrast to previous study that found SETD2 mutations only in EPT ALL patients, none of our SETD2 mutated patients were ETP ALL, two were cortical-T ALL and one was pre-T ALL. All of the patients with SETD2 mutations were alive without the disease at the last follow-up. However, all of the patients were in the high risk group. The patient who had both NOTCH1 and SETD2 mutations responded poorly to prednisone. Although the other two patients without NOTCH1 mutations had good response to prednisone, favorable BM status on day 15 and low MRD on day 33, they had very high MRD levels (0.21% and 0.44% respectively) on day 88. NOTCH1 activating mutations were found in 43.2% of pediatric T-ALL patients enrolled in the CCLG ALL-2008 study with good treatment response while FBXW7 mutation rate was much lower. SETD2 mutation was a recurrent event in pediatric T ALL not only in ETP ALL. It seems that patients with SETD2 mutations have high risk of poor response to chemotherapy regardless of NOTCH1 status. Further studies are needed to find out the prognostic significance of SETD2 mutation in pediatric T ALL. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Clinical Significance of Co-Existence of PHF6 and NOTCH1 mutations in Adult T-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1300-1300
Author(s):  
Zheng Ge ◽  
Min Li ◽  
Lichan Xiao ◽  
Run Zhang ◽  
Jianyong Li
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Synergistic Effect ◽  
Clinical Significance ◽  
Conflicts Of Interest ◽  
Survival Curve ◽  
Lymphoblastic Leukemia ◽  
Mrna Level ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Notch1 Mutations

Abstract Objective: T-cell acute lymphoblastic leukemia (T-ALL) is caused by collaboration of multiple genetic abnormalities in the transformation of T-cell progenitors. PHF6 is founded as a new key tumor suppressor and mutated in T-ALL. The clinical significance of PHF6 mutations has not been fully determined in adult T-ALL. This study aimed to screen the PHF6 mutations in adult T-ALL and explore the associations of PHF6 mutations with other genetic lesions, as well as their clinical relevance in adult T-ALL patients. Methods: We amplified the exons of PHF6, NOTCH1, FBXW7, PTEN and JAK1 following by DNA sequencing to identify the genomic mutations and examined the PHF6 mRNA level by qPCR in adult T-ALL patients. We also analyzed the correlations of PHF6 and NOTCH1 mutations with clinical features using a χ2 test and survival curve using the Kaplan-Meier method. Results: The 27.1% (16/59) PHF6 mutations including 10 novel mutations were detected in Chinese adult T-ALL. Six of 16 (37.5%) were frame-shift mutations, which could result in the deletion of the protein. We also observed PHF6 expression was significantly lower in T-ALL patients with PHF6 mutations compared with wide type cases (0.00423 vs. 0.06464, P=0.035) , indicating PHF6 mutations could be loss of function. Moreover, PHF6 mutation was significantly associated with NOTCH1 mutation(P=0.035). We further analyzed the domains involving co-existence mutations of NOTCH1 with PHF6. The most commonly mutated domains in NOTCH1 co-existed with PHF6 were HD-N only 6/12 (50.0%), followed by HD-C only 2/12(16.7%), PEST only 2/12(16.7%), HD-C+PEST 1/12(8.3%) and HD-N+HD-C 1/12(8.3%), indicating that HD domain (especially HD-N) of NOTCH1 may contribute to the synergistic effect on oncogenesis of the two genes. Furthermore, the patients with co-existence of PHF6 and NOTCH1 mutations had lower hemoglobin and higher incidence of splenomegaly or lymphadenopathy compared to that without co-existence of the mutations (95.0 vs 122.0, P=0.007; 81.8% vs 38.3%, P=0.009; 90.9% vs 44.7%, P=0.006). Importantly, the patients with co-existence of mutations in PHF6 and NOTCH1 (PHF6mutNOTCH1mut) had significant shorter event-free survival (EFS) compared with that without co-existence (non-PHF6mutNOTCH1mut)(2.0 months vs. 12.0 months, P=0.027). Conclusion: PHF6 is inactivated in T-ALL due to its low expression and mutations. PHF6 mutation is co-existed with NOTCH1 mutations, and the patients with PHF6mutNOTCH1mut had a poor prognosis. Our results indicated synergistic effect of PHF6 and NOTCH1 mutations on leukemogenesis and PHF6mutNOTCH1mut may be potential prognostic marker in adult T-ALL. Disclosures No relevant conflicts of interest to declare.

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