Introduction: MYB is a putative oncogene in different type of human solid and hematological tumors. In T-ALL/LBL, rearrangements of MYB (MYB-R) underlying the up-regulation of the gene are, a t(6;7)(q23;q34), that juxtaposes the TRB@ enhancer to MYB full length, a tandem duplication at 6q23, that involves MYB (MYBtdup) and AHI, and double minutes harbouring extra-copies of the gene. Besides rearrangements, a recurrent somatic mutation of MYB has been recently found in pediatric T-ALL/LBL.(1) This study aimed to investigate incidence and distribution of MYB rearrangements and expression in pediatric and adult TALL. Methods: Our integrated molecular-cytogenetic approach (CI-FISH with two assays to study TRB@-MYB and MYBtdup, and SNPa) (2) was used to investigate 319 cases of T-ALL (193 children, 126 adults). The relative expression of MYB was assessed on 61 patients (6 with MYB-R and 55 without, i.e. MYB-wt); in six cases the analysis on paired diagnostic/remission samples could be evaluated. In 56/61, with available data, MYB expression was correlated with overall survival (OS) and probability of relapse (PR) (Cox regression model). Results: Overall, MYB-R were detected in 17 cases (3 TRB@-MYB and 14 MYB tdup) (5.3%). Notably, SNPa was more sensitive than FISH in detection of MYB tdup (7.7% vs. 5%), thus providing the most reliable cytogenetic tool for the diagnosis of this type of CNV. In line with previous report, we identified TRB@-MYB only in pediatric T-ALL (2%), while MYB tdup occurred in both age groups (5% of children and 3% of adults). MYB-R clustered within the HOXA, TLX1/3, or NKX2-1/2- 2 subgroups, suggesting that both TRB@-MYB and MYB tdup behave as secondary oncogenic events, which have a strong association with homeobox deregulated subgroups. qRT-PCR showed a wide range of MYB relative expression in our cohort of T-ALL. The level of MYB expression was significantly higher in MYB-R than MYB-wt cases. However, 20 MYB-wt T-ALL expressed levels of MYB as high as MYBR cases. In keeping with the regulatory positive function of the TAL/LMO complex on MYB transcription, cases with high MYB expression were enriched into the TAL/LMO subgroup. Remarkably, high MYB expression was significantly associated with a lower incidence of relapse (high versus low MYB expression: HR= 0.43; 95% confidence interval: 0.2-0.9, P= 0.03) and showed a trend of better overall survival. Conclusions: MYB deregulation characterizes leukemic blasts of TALL harbouring MYB-R as well as a subgroup of cases with MYB-wt, which mainly belong to the TAL/LMO subgroup. Therefore, high MYB expression should be regarded as a predictive marker of sensitivity for selection of candidates for treatment with MYB inhibitors in clinical trials. Our study also suggests that MYB expression can be used for fine tuning the risk stratification of patients. 1. Liu , Nature Genetics 2017 2. La Starza R, The Journal of Molecular Diagnostics 2020
THE MYB ONCOGENE IN PEDIATRIC AND ADULT T-CELL ALL/LBL
Storlazzi, CT;Tolomeo, D;
2020-01-01
Abstract
Introduction: MYB is a putative oncogene in different type of human solid and hematological tumors. In T-ALL/LBL, rearrangements of MYB (MYB-R) underlying the up-regulation of the gene are, a t(6;7)(q23;q34), that juxtaposes the TRB@ enhancer to MYB full length, a tandem duplication at 6q23, that involves MYB (MYBtdup) and AHI, and double minutes harbouring extra-copies of the gene. Besides rearrangements, a recurrent somatic mutation of MYB has been recently found in pediatric T-ALL/LBL.(1) This study aimed to investigate incidence and distribution of MYB rearrangements and expression in pediatric and adult TALL. Methods: Our integrated molecular-cytogenetic approach (CI-FISH with two assays to study TRB@-MYB and MYBtdup, and SNPa) (2) was used to investigate 319 cases of T-ALL (193 children, 126 adults). The relative expression of MYB was assessed on 61 patients (6 with MYB-R and 55 without, i.e. MYB-wt); in six cases the analysis on paired diagnostic/remission samples could be evaluated. In 56/61, with available data, MYB expression was correlated with overall survival (OS) and probability of relapse (PR) (Cox regression model). Results: Overall, MYB-R were detected in 17 cases (3 TRB@-MYB and 14 MYB tdup) (5.3%). Notably, SNPa was more sensitive than FISH in detection of MYB tdup (7.7% vs. 5%), thus providing the most reliable cytogenetic tool for the diagnosis of this type of CNV. In line with previous report, we identified TRB@-MYB only in pediatric T-ALL (2%), while MYB tdup occurred in both age groups (5% of children and 3% of adults). MYB-R clustered within the HOXA, TLX1/3, or NKX2-1/2- 2 subgroups, suggesting that both TRB@-MYB and MYB tdup behave as secondary oncogenic events, which have a strong association with homeobox deregulated subgroups. qRT-PCR showed a wide range of MYB relative expression in our cohort of T-ALL. The level of MYB expression was significantly higher in MYB-R than MYB-wt cases. However, 20 MYB-wt T-ALL expressed levels of MYB as high as MYBR cases. In keeping with the regulatory positive function of the TAL/LMO complex on MYB transcription, cases with high MYB expression were enriched into the TAL/LMO subgroup. Remarkably, high MYB expression was significantly associated with a lower incidence of relapse (high versus low MYB expression: HR= 0.43; 95% confidence interval: 0.2-0.9, P= 0.03) and showed a trend of better overall survival. Conclusions: MYB deregulation characterizes leukemic blasts of TALL harbouring MYB-R as well as a subgroup of cases with MYB-wt, which mainly belong to the TAL/LMO subgroup. Therefore, high MYB expression should be regarded as a predictive marker of sensitivity for selection of candidates for treatment with MYB inhibitors in clinical trials. Our study also suggests that MYB expression can be used for fine tuning the risk stratification of patients. 1. Liu , Nature Genetics 2017 2. La Starza R, The Journal of Molecular Diagnostics 2020I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
