scholarly journals Proposal of a Genetic Classifier for Risk Group Stratification in Pediatric T-Cell Lymphoblastic Lymphoma Reveals Significant Differences to T-Cell Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2398-2398 ◽  
Author(s):  
Bettina R. Bonn ◽  
Martin Zimmermann ◽  
Sebastian Balbach ◽  
Marius Rohde ◽  
Ilske Oschlies ◽  
...  
Keyword(s):  
T Cell ◽  
Cumulative Incidence ◽  
Risk Group ◽  
Lymphoblastic Leukemia ◽  
Genetic Alterations ◽  
Lymphoblastic Lymphoma ◽  
Treatment Intensity ◽  
Mutational Hotspots ◽  
Group Stratification ◽  
Notch1 Mutations

Abstract Introduction T-cell lymphoblastic lymphoma (T-LBL) represent the second most common subtype of Non-Hodgkin lymphoma (NHL) in children and adolescents. In contrast to other pediatric NHL-subtypes and acute lymphoblastic leukemia (ALL) criteria for the stratification of treatment intensity are lacking in T-LBL. Consequently all patients receive identical treatment intensity resulting in over- and under-treatment of a relevant but not yet characterized subgroup of patients. Recently a genetic classifier for adult T-ALL patients was reported. Whether T-ALL and T-LBL represent one or two diseases remains an ongoing discussion. Whole exome sequencing data of pediatric T-LBL cases now support the hypothesis that T-ALL and T-LBL, despite pathogenic similarities are biologically different. Here we used our large dataset of well defined and uniformly treated pediatric patients with T-LBL to define molecular risk factors of the disease. Methods All pediatric T-LBL patients of the NHL-BFM group with sufficient material available were sequenced for abnormalities in the genes: NOTCH1, FBXW7, NRAS, KRAS, PTEN, PIK3R1, PIK3CA using Sanger sequencing of known mutational hotspots and loss of heterozygosity of chromosome 6q using fragment length analyses. Patients were treated uniformly according to NHL-BFM protocols for T-LBL. Clinical data were available from the data base of the NHL-BFM study center. Accompanying molecular research for the trials NHL-BFM 95 and EURO-LB 02, in which these patients were recruited, has been approved by the ethical committees of the Hannover Medical School and Justus-Liebig University Giessen, Germany. Results The observed frequencies of somatic mutations with 95% confidence intervals were: NOTCH1 61% (51-70%), FBXW7 18% (12-27%), PTEN 15% (9-23%) in 114 analyzed patients, N-RAS + K-RAS 10% (5-18%) in 99 analyzed patients, PIK3R1+PIK3CA in 8% (4-15%) in 107 analyzed patients, and LOH6q 12% (8-17%) in 217 analyzed patients. Detailed evaluation of potential associations of distinct mutation status and clinical characteristics revealed a statistically significant association of NOTCH1 mutations (p=0.006) and FBXW7 mutations (p=0.034) with age below 10 years compared to patients with germline status. All other analyses evaluated for each gene separately taking into account age, gender, stage of disease, CNS disease, bone marrow involvement, mediastinal tumor, and general condition at diagnosis did not identify any statistically significant association. Concerning the concurrence or exclusion of the analyzed alterations, NOTCH1 mutations were significantly associated with FBXW7 mutations (p=0.03). LOH6q positive patients presented significantly more often in cases with NOTCH1 wildtype status (p=0.03) and PTEN mutations and FBXW7 mutations turned out to present mutually exclusive (p=0.03). The analyses concerning patients outcome allowed the proposal of an new genetic classifier defining three risk groups: 1) Good risk group (GR) comprising 39% (35/91) of patients defined by NOTCH1 mutation and no RAS or PIK3 mutation with a cumulative incidence of relapse of 11+5%. 2) Intermediate risk group (IR) with all non-GR and non-HR patients including 46% (42/91) of patients with a cumulative incidence of relapse of 20+6%. 3) High-risk group (HR) of 15% (14/91) of patients defined by NOTCH1 wildtype in combination with PTEN mutation and/or LOH6q positivity associated with a cumulative incidence of relapse of 64+14%. Except for an overrepresentation of patients 10 to 15 years of age in the HR arm, none of tested patients’ characteristic parameters of was associated with risk group. Conclusion Detailed analyses of genetic alterations in pediatric T-LBL revealed relevant somatic mutation frequencies for gene loci of the PTEN/PI3K pathway and the RAS pathway. Together with earlier published results on the prognostic relevance of NOTCH1 mutations and chromosome 6q alterations the analyzed cohort of about 100 uniformly treated pediatric T-LBL patients allowed the definition of a genetic classifier for risk group stratification. This proposed classifier requires prospective validation. The here proposed genetic classifier for T-LBL might be worth to be analyzed in pediatric T-ALL. Interestingly our proposed T-LBL classifier includes some aspects in parallel, but overall differed significantly from the earlier published classifier for adult T-ALL. Disclosures No relevant conflicts of interest to declare.

scholarly journals Genomic and clinical characterization of early T-cell precursor lymphoblastic lymphoma

2021 ◽  
Vol 5 (14) ◽  
pp. 2890-2900
Author(s):  
Xinjie Xu ◽  
Christian N. Paxton ◽  
Robert J. Hayashi ◽  
Kimberly P. Dunsmore ◽  
Stuart S. Winter ◽  
...  
Keyword(s):  
T Cell ◽  
Single Nucleotide Polymorphism Array ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Lymphoblastic Lymphoma ◽  
Cell Precursor ◽  
Genomic Features ◽  
Frequent Absence ◽  
T Lymphoblastic Lymphoma

Abstract Early T-cell precursor phenotype acute lymphoblastic leukemia (ETP-ALL) is a subtype of T-ALL with a unique immunophenotype and genetic abnormalities distinct from conventional T-ALL. A subset of T lymphoblastic lymphoma (T-LLy) also demonstrates the early T-cell precursor immunophenotype and may be a counterpart of ETP-ALL. Unlike ETP-ALL, the incidence, clinical features, and genomic features of ETP-LLy are unknown. We reviewed the immunophenotyping data of 218 T-LLy patients who enrolled in the Children’s Oncology Group AALL0434 clinical trial and identified 9 cases (4%) exhibiting a definitive ETP immunophenotype. We performed single-nucleotide polymorphism array profiling on 9 ETP-LLy and 15 non-ETP T-LLy cases. Compared with non-ETP T-LLy, ETP-LLy showed less frequent deletion of 9p (CKDN2A/B), more frequent deletion of 12p (ETV6) and 1p (RPL22), and more frequent absence of biallelic T-cell receptor γ deletions. Recurrent abnormalities previously described in ETP-ALL such as deletions of 5q and 13q and gain of 6q were not observed in ETP-LLy cases. There were no failures of therapy among the ETP-LLy subtype with a 4-year event-free survival of 100%. Overall, ETP-LLy does not exhibit unifying genetic alterations but shows some distinct genomic features from non-ETP T-LLy suggesting that ETP-LLy may be a distinct entity from non-ETP T-LLy.

scholarly journals Sequential mutations in Notch1, Fbxw7, and Tp53 in radiation-induced mouse thymic lymphomas

Blood ◽  
2012 ◽  
Vol 119 (3) ◽  
pp. 805-809 ◽  
Author(s):  
Kuang-Yu Jen ◽  
Ihn Young Song ◽  
Karl Luke Banta ◽  
Di Wu ◽  
Jian-Hua Mao ◽  
...  
Keyword(s):  
T Cell ◽  
High Frequency ◽  
Single Copy ◽  
Genetic Alterations ◽  
Complete Loss ◽  
Lymphoblastic Lymphoma ◽  
Dependent Manner ◽  
Radiation Induced ◽  
Tp53 Status ◽  
Notch1 Mutations

Abstract T-cell acute lymphoblastic lymphomas commonly demonstrate activating Notch1 mutations as well as mutations or deletions in Fbxw7. However, because Fbxw7 targets Notch1 for degradation, genetic alterations in these genes are expected to be mutually exclusive events in lymphomagenesis. Previously, by using a radiation-induced Tp53-deficient mouse model for T-cell acute lymphoblastic lymphoma, we reported that loss of heterozygosity at the Fbxw7 locus occurs frequently in a Tp53-dependent manner. In the current study, we show that these thymic lymphomas also commonly exhibit activating Notch1 mutations in the proline-glutamic acid-serine-threonine (PEST) domain. Moreover, concurrent activating Notch1 PEST domain mutations and single-copy deletions at the Fbxw7 locus occur with high frequency in the same individual tumors, indicating that these changes are not mutually exclusive events. We further demonstrate that although Notch1 PEST domain mutations are independent of Tp53 status, they are completely abolished in mice with germline Fbxw7 haploinsufficiency. Therefore, Notch1 PEST domain mutations only occur when Fbxw7 expression levels are intact. These data suggest a temporal sequence of mutational events involving these important cancer-related genes, with Notch1 PEST domain mutations occurring first, followed by Fbxw7 deletion, and eventually by complete loss of Tp53.

Screening for leukemia- and clone-specific markers at birth in children with T-cell precursor ALL suggests a predominantly postnatal origin

Blood ◽  
2007 ◽  
Vol 110 (8) ◽  
pp. 3036-3038 ◽  
Author(s):  
Susanna Fischer ◽  
Georg Mann ◽  
Marianne Konrad ◽  
Markus Metzler ◽  
Georg Ebetsberger ◽  
...  
Keyword(s):  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Genetic Alterations ◽  
Specific Marker ◽  
Cell Precursor ◽  
Oncogenic Mutations ◽  
Leukemic Clone ◽  
Sensitive Polymerase Chain Reaction ◽  
Neonatal Blood Spots

Abstract Childhood T-cell precursor acute lymphoblastic leukemia (TCP ALL) is an aggressive disease with a presumably short latency that differs in many biologic respects from B-cell precursor (BCP) ALL. We therefore addressed the issue of in utero origin of this particular type of leukemia by tracing oncogenic mutations and clone-specific molecular markers back to birth. These markers included various first- and second-hit genetic alterations (TCRD-LMO2 breakpoint regions, n = 2; TAL1 deletions, n = 3; Notch1 mutations, n = 1) and nononcogenic T-cell receptor rearrangements (n = 13) that were derived from leukemias of 16 children who were 1.5 to 11.2 years old at diagnosis of leukemia. Despite highly sensitive polymerase chain reaction (PCR) approaches (1 cell with a specific marker among 100 000 normal cells), we identified the leukemic clone in the neonatal blood spots in only 1 young child. These data suggest that in contrast to BCP ALL most TCP ALL cases are initiated after birth.

scholarly journals T-cell lymphoblastic lymphoma and leukemia: different diseases from a common premalignant progenitor?

2020 ◽  
Vol 4 (14) ◽  
pp. 3466-3473
Author(s):  
Emma Kroeze ◽  
Jan L. C. Loeffen ◽  
Vera M. Poort ◽  
Jules P. P. Meijerink
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Clinical Presentation ◽  
Lymphoblastic Leukemia ◽  
Precursor Cell ◽  
Lymphoblastic Lymphoma ◽  
Leukemia Cells ◽  
Driver Mutations ◽  
Lymphoid Tissues ◽  
Genetic Profiles

Abstract T-cell lymphoblastic lymphoma (T-LBL) and lymphoblastic leukemia (T-ALL) represent malignancies that arise from the transformation of immature precursor T cells. Similarities in T-LBL and T-ALL have raised the question whether these entities represent 1 disease or reflect 2 different diseases. The genetic profiles of T-ALL have been thoroughly investigated over the last 2 decades, whereas fairly little is known about genetic driver mutations in T-LBL. Nevertheless, the comparison of clinical, immunophenotypic, and molecular observations from independent T-LBL and T-ALL studies lent strength to the theory that T-LBL and T-ALL reflect different presentations of the same disease. Alternatively, T-LBL and T-ALL may simultaneously evolve from a common malignant precursor cell, each having their own specific pathogenic requirements or cellular dependencies that differ among stroma-embedded blasts in lymphoid tissues compared with solitary leukemia cells. This review aims to cluster recent findings with regard to clinical presentation, genetic predisposition, and the acquisition of additional mutations that may give rise to differences in gene expression signatures among T-LBL and T-ALL patients. Improved insight in T-LBL in relation to T-ALL may further help to apply confirmed T-ALL therapies to T-LBL patients.

scholarly journals Deletion of Pten in CD45-expressing cells leads to development of T-cell lymphoblastic lymphoma but not myeloid malignancies

Blood ◽  
2016 ◽  
Vol 127 (15) ◽  
pp. 1907-1911 ◽  
Author(s):  
Cristina Mirantes ◽  
Maria Alba Dosil ◽  
David Hills ◽  
Jian Yang ◽  
Núria Eritja ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Mouse Model ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Cells ◽  
Hematologic Malignancies ◽  
Lymphoblastic Lymphoma ◽  
Key Points ◽  
Pten Deletion ◽  
Cell Acute Lymphoblastic Leukemia

Key Points CD45-driven expression of Cre generates the first mouse model that allows specific and exclusive deletion of Pten in hematopoietic cells. Pten deletion in CD45-expressing cells causes T-cell acute lymphoblastic leukemia, but no other hematologic malignancies.

Frequency of NUP214-ABL1 Oncogene in Patients with T-Cell Acute Lymphoblastic Leukemia (T-ALL) and Analysis of the Activity of Imatinib and Nilotinib in NUP214-ABL1-Expressing T-ALL Cell Lines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 710-710
Author(s):  
Alfonso Quintas-Cardama ◽  
Weigang Tong ◽  
Taghi Manshouri ◽  
Jan Cools ◽  
D. Gary Gilliland ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Lymphoblastic Leukemia ◽  
Fusion Transcript ◽  
Lymphoblastic Lymphoma ◽  
Abl Kinase ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitory Activity

Abstract The fusion of ABL1 with BCR results in the hybrid BCR-ABL1 oncogene that encodes the constitutively active Bcr-Abl tyrosine kinase encountered in the majority of patients with chronic myeloid leukemia (CML) and in approximately 30% of pts with B-cell acute lymphoblastic leukemia (B-ALL). Recently, the episomal amplification of ABL1 has been described in 6% of pts with T-ALL (Nat Genet2004;36:1084–9). Molecular analysis demonstrated the oncogenic fusion of ABL1 with the nuclear pore complex protein NUP214 (NUP214-ABL1). We screened 29 pts with T-cell lymphoblastic lymphoma (T-LBL) and T-ALL for the presence of the NUP214-ABL1 fusion transcript by RT-PCR using specific primers for the 5 different transcripts thus far described. Three (10%) pts were found to express this fusion transcript, including 2 with T lymphoblastic lymphoma (NUP214 exon 31) and 1 with T-ALL (NUP214 exon 29). This was confirmed by direct sequencing in all cases. All pts received therapy with hyperCVAD and achieved a complete remission (CR). However, 2 of them died 6 and 9 months into therapy, respectively. One other pt remains in CR (19+ months) by morphologic and flow cytometry criteria. However, NUP214-ABL1 is still detectable in peripheral blood by nested PCR, thus suggesting minimal residual disease (MRD). We then studied the activity of the tyrosine kinase inhibitors imatinib and nilotinib in the NUP214-ABL1-expressing cell lines PEER and BE-13. Although PEER and BE-13 cell viability was reduced with both agents, the IC50 was almost 10-fold higher for imatinib (643 nM) than for nilotinib (68 nM) (F test, p<0.001), which parallels the 10− to 30− fold higher Abl kinase inhibitory activity of nilotinib compared to imatinib in BCR-ABL-expressing cells. Nilotinib also potently inhibited the cell proliferation of BE-13 cells (IC50 131 nM). In contrast, Jurkat cells, a T-ALL cell line which does not carry NUP214-ABL1, were remarkably resistant to both imatinib and nilotinib with an IC50 values greater than 5 μM indicating that the cytotoxicity mediated by both TKIs is not related to a general toxic effect on T-ALL cell lines. The inhibition of cellular proliferation by imatinib and nilotinib was associated with a dose- and time-dependent induction of apoptosis in both PEER and BE-13 cells. In Western blotting, higher inhibition of phospho-Abl and phospho-CRKL (a surrogate of Bcr-Abl kinase status) was observed in PEER cells upon exposure to nilotinib as compared with imatinib at their respective IC50 concentrations for cell growth inhibition. We conclude that NUP214-ABL1 can be detected in 10% of pts with T-cell malignancies and its detection can be used as a sensitive marker of MRD. Imatinib and nilotinib potently inhibits the growth of NUP214-ABL1-expressing cells. Given the higher Abl kinase inhibitory activity of nilotinib with respect to imatinib, this agent must be further investigated in clinical studies targeting patients with T-ALL and T-LBL expressing the NUP214-ABL1 fusion kinase.

Haploidentical Hematopoietic Stem Cell Transplantation without In Vitro T Cell Depletion for Treatment of Hematological Malignancies in Children.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5069-5069
Author(s):  
Daihong Liu ◽  
Xiao Jun Huang ◽  
Kaiyan Liu ◽  
Lanping Xu ◽  
Huan Chen ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Hematopoietic Stem Cell ◽  
Cumulative Incidence ◽  
Risk Group ◽  
T Cell Depletion ◽  
Hematopoietic Stem

Abstract Objective: To evaluate the efficacy and safety of haploidentical hematopoietic stem cell transplantation (HCT) for children with donors from family members. Patients and methods: Forty-two children under fourteen years old with hematologic malignancies underwent haploidentical HCT. The outcome was analyzed. Results: Four (9.5%) of the forty-two patients/donor pairs mismatched in one HLA locus, fifteen (35.7%) pairs in two loci and twenty three (54.8%) in three loci. They were followed up for a median of 612 (40–1779) days. All patients achieved stable engraftment. The cumulative incidence of acute graft-versus-host disease (GVHD) grade 2–4 was 57.2%, and that of grade 3–4 was 13.8%. The cumulative incidence of total and extensive chronic GVHD was 56.7% and 29.5%, respectively. The probability of leukemia-free survival was 65.1% in standard-risk group and 49.6% in high-risk group. Fourteen patients died, four from infection, six from relapse of leukemia, two from heart failure, one from severe acute GVHD, and one from lymphoproliferative disorders. The probability of relapse was 13.8% at 1 year and 27.9% at 2 year after transplantation. Conclusion: The results in this study encourage extending the haploidentical HCT without T-cell depletion to children with an indication for transplantation.

C-Myc, but Not Akt, Can Substitute for Notch in Lymphomagenesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 7-7
Author(s):  
Mark Y Chiang ◽  
M. Eden Childs ◽  
Candice Romany ◽  
Olga Shestova ◽  
Jon Aster ◽  
...  
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
Selective Pressure ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Gamma Secretase ◽  
Growth And Survival ◽  
Strong Selective Pressure ◽  
Human T Cell ◽  
Notch1 Mutations

Abstract Abstract 7 Notch signaling is activated in ∼70% of human T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) samples and many human and mouse T-ALL cell lines require Notch signals for growth and survival. To gain insight into the role of Notch during induction of T-ALL, we used a fully penetrant, conditional, transgenic KrasG12D mouse model in which ∼80% of T-ALLs acquire activating Notch1 mutations in the endogenous locus. We crossed mice bearing this transgene with Rosa26-DNMAMLf/f mice, which conditionally express the pan-Notch inhibitor DNMAML. T-ALL developed in these mice despite the expression of DNMAML throughout T-cell development. ∼75% of T-ALL tumors acquired activating Notch1 mutations and suppressed expression of DNMAML, which is consistent with frequent “escape” of Notch from inhibition for efficient T-ALL development. We next compared T-ALL cells that lacked DNMAML expression with T-ALL cells that continued to express DNMAML. T-ALL cells lacking DNMAML expressed the direct Notch target c-Myc at higher levels, proliferated at a higher rate, and contained ∼10-fold higher levels of leukemia-initiating cells. Moreover, DNMAML-positive T-ALLs lost DNMAML after transfer into secondary recipients. These data underscore the strong selective pressure for Notch signals during generation and maintenance of T-ALL. We next sought a mechanistic answer for the strong selective pressure for Notch activation. c-Myc and Akt have both been posited to be critical targets of oncogenic Notch signals. To compare the relative contributions of c-Myc and Akt to lymphomagenesis, we overexpressed c-Myc and activated AKT in the KrasG12D-driven mouse model. T-ALLs induced by KrasG12D and Akt acquired activating Notch1 mutations in ∼70% of tumors, which were sensitive to Notch inhibitors (gamma-secretase inhibitors [GSI]). In contrast, T-ALLs induced by KrasG12D and c-Myc did not acquire Notch1 mutations and were resistant to GSI. We conclude that upregulation of c-Myc is sufficient to substitute for Notch in lymphomagenesis, whereas activation of Akt signaling is not. These data identify c-Myc not AKT as the driving force behind Notch-induced lymphomagenesis. These data emphasize the Notch/c-Myc axis as an attractive, rational, therapeutic target in T-ALL. Disclosures: No relevant conflicts of interest to declare.

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