NUP214-ABL1 in adult T-ALL: the GMALL study group experience

Blood ◽  
2006 ◽  
Vol 108 (10) ◽  
pp. 3556-3559 ◽  
Author(s):  
Thomas Burmeister ◽  
Nicola Gökbuget ◽  
Richard Reinhardt ◽  
Harald Rieder ◽  
Dieter Hoelzer ◽  
...  
Keyword(s):  
T Cell ◽  
Kinase Inhibitors ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Prognostic Impact ◽  
Significant Difference ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Pcr Method ◽  
Polymerase Chain

Abstract The NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia (T-ALL) has recently been identified as a possible target for imatinib and related tyrosine kinase inhibitors, but exact data regarding the prognostic impact and frequency of the several putative NUP214-ABL1 mRNA transcripts are still missing. We investigated 279 adult patients with T-ALL treated within the framework of the GMALL 5/93 and 6/99 therapy trials for NUP214-ABL1 by using a novel multiplex real-time, quantitative polymerase chain reaction (PCR). Eleven (3.9%) patients were NUP214-ABL1 positive, and 5 different transcripts were observed; 8 patients had a thymic immunophenotype, 1 had an early T-cell immunophenotype, and 2 had a mature T-cell immunophenotype. NUP214-ABL1-positive and -negative patients did not differ significantly in their major clinical features. In contrast to previous reports suggesting an adverse clinical course for NUP214-ABL1-positive patients, no significant difference in overall survival was observed. Based on the results, we have established and tested a novel PCR method for simplified detection of the NUP214-ABL1 fusion gene.

scholarly journals Heterogeneous patterns of amplification of the NUP214-ABL1 fusion gene in T-cell acute lymphoblastic leukemia

Leukemia ◽  
2008 ◽  
Vol 23 (1) ◽  
pp. 125-133 ◽  
Author(s):  
C Graux ◽  
◽  
M Stevens-Kroef ◽  
M Lafage ◽  
N Dastugue ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Cell Acute Lymphoblastic Leukemia

scholarly journals Detection of minimal residual disease in T-cell acute lymphoblastic leukemia using polymerase chain reaction predicts impending relapse

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 739-747 ◽  
Author(s):  
GA Neale ◽  
J Menarguez ◽  
GR Kitchingman ◽  
TJ Fitzgerald ◽  
M Koehler ◽  
...  
Keyword(s):  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pcr Amplification ◽  
Leukemic Cells ◽  
Chain Reaction ◽  
Leukemic Clone ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Polymerase Chain

Abstract After achieving remission, approximately one-third of patients with T- cell acute lymphoblastic leukemia (T-ALL) relapse due to the resurgence of residual leukemic cells that cannot be detected in remission by morphologic methods. Thus, the early detection of residual disease is highly desirable to monitor the efficacy of therapy, or to institute an alternative mode of therapy. Toward this aim, we have examined the applicability of polymerase chain reaction (PCR) amplification in the detection of minimal residual disease (MRD) in bone marrow samples from patients with T-ALL in morphologic remission. Two different approaches were taken to identify leukemic clone-specific sequences that could be used as targets for PCR amplification. The first technique used T-cell receptor-delta (TCR-delta) gene rearrangements that were sequenced directly after PCR amplification of leukemic DNA. This method was successful in generating clone-specific probes for 76% of T-ALL patients screened. An alternative method was used to clone and sequence a TCR-beta chain gene from leukemic cells to generate a specific probe. The PCR assays that we used were specific for each patient's leukemic clone, and were capable of routinely detecting one leukemic cell in 10(4) normal cells. Using these sensitive PCR-based assays, we found no evidence for persistence of the leukemic clone in any of the bone marrow samples from four T-ALL patients who are in long-term (3.9 + to 8.1 + years) remission. In contrast, we detected residual disease in clinical remission samples from two patients who subsequently relapsed. In one patient, where we had appropriate samples, we observed a dramatic expansion of the leukemic clone 3 months before clinical relapse. These results suggest that PCR-based assays for detection of MRD in T-ALL patients have great potential in predicting impending relapse, and in determining the efficacy of the anti-leukemic therapy. These methods may also allow the identification of long-term survivors.

scholarly journals Detection of minimal residual disease in T-cell acute lymphoblastic leukemia using polymerase chain reaction predicts impending relapse

Blood ◽  
1991 ◽  
Vol 78 (3) ◽  
pp. 739-747 ◽  
Author(s):  
GA Neale ◽  
J Menarguez ◽  
GR Kitchingman ◽  
TJ Fitzgerald ◽  
M Koehler ◽  
...  
Keyword(s):  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pcr Amplification ◽  
Leukemic Cells ◽  
Chain Reaction ◽  
Leukemic Clone ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Polymerase Chain

After achieving remission, approximately one-third of patients with T- cell acute lymphoblastic leukemia (T-ALL) relapse due to the resurgence of residual leukemic cells that cannot be detected in remission by morphologic methods. Thus, the early detection of residual disease is highly desirable to monitor the efficacy of therapy, or to institute an alternative mode of therapy. Toward this aim, we have examined the applicability of polymerase chain reaction (PCR) amplification in the detection of minimal residual disease (MRD) in bone marrow samples from patients with T-ALL in morphologic remission. Two different approaches were taken to identify leukemic clone-specific sequences that could be used as targets for PCR amplification. The first technique used T-cell receptor-delta (TCR-delta) gene rearrangements that were sequenced directly after PCR amplification of leukemic DNA. This method was successful in generating clone-specific probes for 76% of T-ALL patients screened. An alternative method was used to clone and sequence a TCR-beta chain gene from leukemic cells to generate a specific probe. The PCR assays that we used were specific for each patient's leukemic clone, and were capable of routinely detecting one leukemic cell in 10(4) normal cells. Using these sensitive PCR-based assays, we found no evidence for persistence of the leukemic clone in any of the bone marrow samples from four T-ALL patients who are in long-term (3.9 + to 8.1 + years) remission. In contrast, we detected residual disease in clinical remission samples from two patients who subsequently relapsed. In one patient, where we had appropriate samples, we observed a dramatic expansion of the leukemic clone 3 months before clinical relapse. These results suggest that PCR-based assays for detection of MRD in T-ALL patients have great potential in predicting impending relapse, and in determining the efficacy of the anti-leukemic therapy. These methods may also allow the identification of long-term survivors.

Prognostic and oncogenic relevance of TLX1/HOX11 expression level in T-ALLs

Blood ◽  
2007 ◽  
Vol 110 (7) ◽  
pp. 2324-2330 ◽  
Author(s):  
Julie Bergeron ◽  
Emmanuelle Clappier ◽  
Isabelle Radford ◽  
Agnès Buzyn ◽  
Corinne Millien ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Event Free Survival ◽  
Chain Reaction ◽  
Free Survival ◽  
Maturation Arrest ◽  
Prognostic Analysis ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Polymerase Chain

TLX1 is a homeodomain transcription factor generally associated with a favorable outcome in T-cell acute lymphoblastic leukemia (T-ALL). However, the molecular mechanisms of TLX1 deregulation remain unclear and various transcript levels in the absence of 10q24 abnormalities have been reported. A reproducible and accurate delineation of TLX1+ T-ALL will be necessary for proper therapeutic stratification. We have studied 264 unselected T-ALLs (171 adults and 93 children) and show that T-ALLs expressing high levels of TLX1 (n = 35, 13%), defined as a real-time quantitative polymerase chain reaction (RQ-PCR) level of TLX1 greater than 1.00 ABL, form a homogeneous oncogenic group, based on their uniform stage of maturation arrest and oncogenetic and transcriptional profiles. Furthermore, TLX1-high T-ALLs harbor molecular TLX1 locus abnormalities in the majority (31/33), a proportion largely underestimated by standard karyotypic screening. T-ALLs expressing TLX1 at lower levels (n = 57, 22%) do not share these characteristics. Prognostic analysis within the adult LALA94 and GRAALL03 prospective protocols demonstrate a better event-free survival (P = .035) and a marked trend for longer overall survival (P = .059) for TLX1-high T-ALLs, while the expression of lower levels of TLX1 does not impact on prognosis. We propose that TLX1+ T-ALLs be defined as cases expressing TLX1/ABL ratios greater than 1 and/or demonstrating TLX1 rearrangement. Therapeutic modification should be considered for those patients.

scholarly journals Recent advances on blinatumomab for acute lymphoblastic leukemia

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Juanjuan Zhao ◽  
Yongping Song ◽  
Delong Liu
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Kinase Inhibitors ◽  
Residual Disease ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
The Past ◽  
Drug Conjugates ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Although complete remission rate of B cell acute lymphoblastic leukemia (B-ALL) has improved significantly over the past few decades, patients with relapsed/refractory ALL still have dismal outcome. Tyrosine kinase inhibitors, antibody–drug conjugates and chimeric antigen receptor T cell therapy are changing the therapy landscape for B- ALL. Blinatumomab, a bi-specific T cell engager, has been approved for patients with relapsed/refractory and minimal residual disease positive B-ALL. This review summarized data from recent clinical trials of blinatumomab for B-ALL treatment.

scholarly journals Fusion of EML1 to ABL1 in T-cell acute lymphoblastic leukemia with cryptic t(9;14)(q34;q32)

Blood ◽  
2005 ◽  
Vol 105 (12) ◽  
pp. 4849-4852 ◽  
Author(s):  
Kim De Keersmaecker ◽  
Carlos Graux ◽  
Maria D. Odero ◽  
Nicole Mentens ◽  
Riet Somers ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Coiled Coil ◽  
Signal Transducers ◽  
Extracellular Signal ◽  
Cell Acute Lymphoblastic Leukemia

Abstract The BCR-ABL1 fusion kinase is frequently associated with chronic myeloid leukemia and B-cell acute lymphoblastic leukemia but is rare in T-cell acute lymphoblastic leukemia (T-ALL). We recently identified NUP214-ABL1 as a variant ABL1 fusion gene in 6% of T-ALL patients. Here we describe the identification of another ABL1 fusion, EML1-ABL1, in a T-ALL patient with a cryptic t(9;14)(q34;q32) associated with deletion of CDKN2A (p16) and expression of TLX1 (HOX11). Echinoderm microtubule-associated protein-like 1-Abelson 1 (EML1-ABL1) is a constitutively phosphorylated tyrosine kinase that transforms Ba/F3 cells to growth factor-independent growth through activation of survival and proliferation pathways, including extracellular signal-related kinase 1/2 (Erk1/2), signal transducers and activators of transcription 5 (Stat5), and Lyn kinase. Deletion of the coiled-coil domain of EML1 abrogated the transforming properties of the fusion kinase. EML1-ABL1 and breakpoint cluster region (BCR)-ABL1 were equally sensitive to the tyrosine kinase inhibitor imatinib. These data further demonstrate the involvement of ABL1 fusions in the pathogenesis of T-ALL and identify EML1-ABL1 as a novel therapeutic target of imatinib. (Blood. 2005;105:4849-4852)

scholarly journals Ku70 is Associated with the Frequency of Chromosome Translocation in Human Lymphocytes After Radiation and T-Cell Acute Lymphoblastic Leukemia

2021 ◽  
Author(s):  
Zhenbo Cheng ◽  
Yupeng Wang ◽  
Lihuang Guo ◽  
Jiancheng Li ◽  
Wei Zhang ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Protein Level ◽  
Lymphoblastic Leukemia ◽  
Quantitative Polymerase Chain Reaction ◽  
Human Lymphocytes ◽  
Chromosome Translocation ◽  
X Rays ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Chemical Inhibition

Abstract Background: Chromosome translocation is one of the most common chromosomal causes to T-cell acute lymphoblastic leukemia (T-ALL). Ku70 is one of the key factors of error-prone DNA repair that may end in translocation. So far, the direct correlation between Ku70 and translocation has not been assessed. Our study aimed to investigate the association of Ku70 and translocation in human lymphocytes after radiation and T-ALL. Methods: Peripheral blood lymphocytes (PBLs) from volunteers and human lymphocyte cell line AHH-1were irradiated with X-rays to form chromosome translocations. The frequency of translocation was detected by fluorescence in situ hybridization (FISH), meanwhile, the expression of Ku70 was also detected by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Furthermore, Ku70 interference, overexpression and chemical inhibition were used in AHH-1 cell lines to confirm the correlation. Finally, we detected the expression of Ku70 in T-ALL samples with or without translocation. Results: Expression of Ku70 and frequencies of translocation were both significantly increased in PBLs after irradiated by X-rays, and a positive correlation between the expression (both mRNA and protein level) of Ku70 and the frequency of translocation was detected (r = 0.4877, P = 0.004; r = 0.3038, P = 0.0358 respectively). Moreover, Ku70 interference decreased the frequency of translocations while the frequency of translocations was not significantly affected after Ku70 overexpression. The expression of Ku70 and frequencies of translocation were both significantly increased in cells after irradiated combined with chemical inhibition (P <0.01). The protein level and mRNA level of Ku70 in T-ALL with translocation were significantly higher than T-ALL with normal karyotype (P = 0.009, P = 0.049 respectively). Conclusions: Ku70 is closely associated with the frequency of chromosome translocation in human lymphocytes after radiation and T-ALL. Ku70 might be a radiation damage biomarker and a potential tumor therapy target.

Cloning of AML1-LAF4 Fusion Gene in Childhood T-Cell Acute Lymphoblastic Leukemia with t(2;21)(q11;q22) by Bubble PCR Method for cDNA.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 983-983
Author(s):  
Yoshiaki Chinen ◽  
Tomohiko Taki ◽  
Kazuhiro Nishida ◽  
Daisuke Shimizu ◽  
Takashi Okuda ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Acute Leukemia ◽  
Fusion Proteins ◽  
Lymphoblastic Leukemia ◽  
Common Mechanism ◽  
Fusion Partner ◽  
Fusion Transcripts ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Pcr Method

Abstract The AML1/RUNX1 gene is frequently rearranged by chromosomal translocations in acute leukemia. To date, more than 10 fusion genes involving AML1 have been cloned, such as AML1-MTG8 in acute myeloid leukemia (AML) with t(8;21), AML1-EVI1/MDS1 in therapy-related AML/myelodysplastic syndrome with t(3;21), and TEL/ETV6-AML1 in B precursor ALL with t(12;21). We analyzed a pediatric patient having T-cell acute lymphoblastic leukemia (T-ALL) with t(2;21)(q11;q22), and identified that the LAF4 gene on 2q11.2–12 was fused to the AML1 gene on 21q22 using the bubble PCR method for cDNA. The genomic breakpoints were within intron 7 of AML1 and intron 7 of LAF4 resulting in the in-frame fusion of exon 7 of AML1 and exon 8 of LAF4. LAF4 gene is a member of the AF4/FMR2 family, and was previously identified as a fusion partner of MLL in B-precursor ALL with t(2;11)(q11;q23), although AML1-LAF4 was in T-ALL. LAF4 is the first gene fused with both AML1 and MLL in acute leukemia. These findings provide new insights into the common mechanism of AML1 and MLL fusion proteins in the pathogenesis of ALL. In this study, we first applied the panhandle PCR method that is usually used for cloning the fusion partners of MLL or NUP98; however, no fusion transcripts could be obtained. Therefore, we searched for another method for cloning the fusion transcripts and successfully adapted the bubble PCR method for cloning the novel AML1-LAF4 fusion transcript. To date, bubble PCR has been performed for cloning unknown genomic fusion points but not fusion cDNAs. Using double-strand cDNA, we could apply the bubble PCR method for cloning fusion cDNA with rare non-specific products. Bubble PCR for cDNA could amplify in both 5′ to 3′ and 3′ to 5′ directions of the gene or transcript and handle any exons fused to unknown partners for amplification easily. This method will contribute to identifying numerous novel translocation partners more easily, and these findings may help to clarify the role of the fusion proteins in leukemogenesis.

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