Design of a Comprehensive Fluorescence in Situ Hybridization Assay for Genetic Classification of T-Cell Acute Lymphoblastic Leukemia

Starza, Roberta La; Pierini, Valentina; Pierini, Tiziana; Nofrini, Valeria; Matteucci, Caterina; Arniani, Silvia; Moretti, Martina; Fernandez, Anair Graciela Lema; Pellanera, Fabrizia; Giacomo, Danika Di; Storlazzi, T.; Vitale, Antonella; Gorello, Paolo; Sammarelli, Gabriella; Roti, Giovanni; Basso, Giuseppe; Chiaretti, Sabina; Foà, Robin; Schwab, Claire; Harrison, Christine J.; Vlierberghe, Pieter Van; Mecucci, Cristina

doi:10.1016/j.jmoldx.2020.02.004

Cited by 23 publications

(40 citation statements)

References 45 publications

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“…We carried out extensive molecular‐cytogenetic screening of 331 previously published T‐ALL 13 to assess incidence, types, and distribution, of MYB abnormalities in pediatric and adult cases. Confirming the low incidence reported in pediatric T‐ALL, 10 MYB E14 hot‐spot mutations were not found in our cases.…”

Section: Discussionmentioning

confidence: 99%

“…The study was carried out on a cohort of 331 patients with T‐ALL, previously reported 13 . There were 191 children and 140 adults (Table 1).…”

Section: Methodsmentioning

confidence: 99%

“…Molecular‐cytogenetics detected “type A" abnormalities in 237 cases which were classified as TAL/LMO (= 72), HOXA ( n = 80), TLX3 ( n = 35), TLX1 ( n = 32), NKX2‐1/NKX2‐2 ( n = 15), and MEF2C ( n = 3) 14 . Ninety‐four T‐ALL remained undetermined 13 CDKN2AB mono‐ or bi‐ allelic deletions were detected 195/331 (59%) cases. NOTCH1/FBXW7 hot spot mutations were found in 130/205 T‐ALL cases for which DNA was available (63%).…”

Section: Methodsmentioning

confidence: 99%

“…Probes for the centromeric region of chromosome 6 and for genes/loci mapping to 6q15‐q21 were selected to fully characterize cases in which MYB FISH probe showed abnormal hybridization patterns. The analysis was carried out on 100‐150 nuclei using a fluorescence microscope (Olympus BX61) 13 …”

Section: Methodsmentioning

confidence: 99%

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MYB rearrangements and over‐expression in T‐cell acute lymphoblastic leukemia

Bardelli

Arniani

Pierini

et al. 2021

Genes Chromosomes & Cancer

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We investigated MYB rearrangements (MYB‐R) and the levels of MYB expression, in 331 pediatric and adult patients with T‐cell acute lymphoblastic leukemia (T‐ALL). MYB‐R were detected in 17 cases and consisted of MYB tandem duplication (tdup) (= 14) or T cell receptor beta locus (TRB)‐MYB (= 3). As previously reported, TRB‐MYB was found only in children (1.6%) while MYB tdup occurred in both age groups, although it was slightly more frequent in children (5.2% vs 2.8%). Shared features of MYB‐R T‐ALL were a non‐early T‐cell precursor (ETP) phenotype, a high incidence of NOTCH1/FBXW7 mutations (81%) and CDKN2AB deletions (70.5%). Moreover, they mainly belonged to HOXA (=8), NKX2‐1/2‐2/TLX1 (=4), and TLX3 (=3) homeobox‐related subgroups. Overall, MYB‐R cases had significantly higher levels of MYB expression than MYB wild type (MYB‐wt) cases, although high levels of MYB were detected in ~ 30% of MYB‐wt T‐ALL. Consistent with the transcriptional regulatory networks, cases with high MYB expression were significantly enriched within the TAL/LMO subgroup (P = .017). Interestingly, analysis of paired diagnosis/remission samples demonstrated that a high MYB expression was restricted to the leukemic clone. Our study has indicated that different mechanisms underlie MYB deregulation in 30%‐40% of T‐ALL and highlighted that, MYB has potential as predictive/prognostic marker and/or target for tailored therapy.

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Section: Discussionmentioning

confidence: 99%

“…The study was carried out on a cohort of 331 patients with T‐ALL, previously reported 13 . There were 191 children and 140 adults (Table 1).…”

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

MYB rearrangements and over‐expression in T‐cell acute lymphoblastic leukemia

Bardelli

Arniani

Pierini

et al. 2021

Genes Chromosomes & Cancer

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“…several biological studies have demonstrated a high genetic heterogeneity of these diseases; however, they have also enabled identification of druggable genetic alterations and potentially targetable pathways. 15-17 Novel potential therapeutic approaches for patients with R/R T-ALL/T-LBL, including gamma-secretase inhibitors, BCL-2 inhibitors, mTor inhibitors, and monoclonal antibodies (such as daratumumab) have demonstrated promising preliminary results.However, none of these agents have received approval for clinical use 1,5,18,19. Stem cell transplant remains the sole potentially curative option for these patients, but there is limited information regarding the feasibility and outcomes of SCT in the adult R/R T-ALL/T-LBL population 20.…”

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confidence: 99%

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study

et al. 2020

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The outcome of relapsed or refractory (R/R) T‐cell acute lymphoblastic leukemia/lymphoma (T‐ALL/T‐LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T‐ALL/T‐LBL, but the information to support its use is based on limited available data. The aim of this observational phase four study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T‐ALL/T‐LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post‐SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18‐74 years), 73% were male, 77 had a diagnosis of T‐ALL and 41 of T‐LBL, and 65/118 (55%) had received more than two lines of therapy. The median number of nelarabine cycles was two (range 1‐4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs 22%, log‐rank P < .001). The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy‐five patients (64%) experienced one or more drug‐related adverse events (AE). Grade III‐IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III‐IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T‐ALL/T‐LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III‐IV neurological AE.

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Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

Almeida,

T'Sas,

Pagliaro

et al. 2024

HemaSphere

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T‐lineage acute lymphoblastic leukemia (T‐ALL) is an aggressive hematological malignancy that accounts for 10%–15% of pediatric and 25% of adult ALL cases. Although the prognosis of T‐ALL has improved over time, the outcome of T‐ALL patients with primary resistant or relapsed leukemia remains poor. Therefore, further progress in the treatment of T‐ALL requires a better understanding of its biology and the development of more effective precision oncologic therapies. The proto‐oncogene MYB is highly expressed in diverse hematologic malignancies, including T‐ALLs with genomic aberrations that further potentiate its expression and activity. Previous studies have associated MYB with a malignant role in the pathogenesis of several cancers. However, its role in the induction and maintenance of T‐ALL remains relatively poorly understood. In this study, we found that an increased copy number of MYB is associated with higher MYB expression levels, and might be associated with inferior event‐free survival of pediatric T‐ALL patients. Using our previously described conditional Myb overexpression mice, we generated two distinct MYB‐driven T‐ALL mouse models. We demonstrated that the overexpression of Myb synergizes with Pten deletion but not with the overexpression of Lmo2 to accelerate the development of T‐cell lymphoblastic leukemias. We also showed that MYB is a dependency factor in T‐ALL since RNA interference of Myb blocked cell cycle progression and induced apoptosis in both human and murine T‐ALL cell lines. Finally, we provide preclinical evidence that targeting the transcriptional activity of MYB can be a useful therapeutic strategy for the treatment of T‐ALL.

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Design of a Comprehensive Fluorescence in Situ Hybridization Assay for Genetic Classification of T-Cell Acute Lymphoblastic Leukemia

Cited by 23 publications

References 45 publications

MYB rearrangements and over‐expression in T‐cell acute lymphoblastic leukemia

MYB rearrangements and over‐expression in T‐cell acute lymphoblastic leukemia

Nelarabine as salvage therapy and bridge to allogeneic stem cell transplant in 118 adult patients with relapsed/refractory T‐cell acute lymphoblastic leukemia/lymphoma. A CAMPUS ALL study

Myb overexpression synergizes with the loss of Pten and is a dependency factor and therapeutic target in T‐cell lymphoblastic leukemia

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