Abstract:DUX4-rearrangement (DUX4r) is a recently discovered recurrent genomic lesion reported in 4–7% of childhood B cell acute lymphoblastic leukaemia (B-ALL) cases. This subtype has favourable outcomes, especially in children and adolescents treated with intensive chemotherapy. The fusion most commonly links the hypervariable IGH gene to DUX4 a gene located within the D4Z4 macrosatellite repeat on chromosome 4, with a homologous polymorphic repeat on chromosome 10. DUX4r is cryptic to most standard diagnostic techni… Show more
“…The B-progenitor ALL subtype is characterized by deregulation of the homeobox transcription factor gene DUX4 , which is reported in 4–7% of childhood B-ALL cases [ 225 ]. It was indicated that the DUX4 rearrangement is a clonal event acquired in the early stage of leukemogenesis [ 226 ].…”
Section: Genetic Biomarkersmentioning
confidence: 99%
“…DUX4 is present in the D4Z4 repeats of the subtelomeric region of chromosome 4q or the homologous region at 10q. However, D4Z4 repeats go through the process of insertion to the IGH locus on chromosome 14 [ 225 , 228 ]. This rearrangement leads to disruption of the highly conserved C terminus of DUX4 , which is necessary for the process of DUX4 oncogenic activation.…”
Section: Genetic Biomarkersmentioning
confidence: 99%
“…Additionally, AYA patients presented longer disease-free survival after complete remission (CR) [ 229 ]. In the context of applied intensive chemotherapy, it appears that DUX4 -r in B-ALL patients presents favorable outcomes [ 225 ]. The differences in prognosis between pediatric and adult patients were highlighted with better outcomes in the first group of patients [ 130 , 219 ].…”
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.
“…The B-progenitor ALL subtype is characterized by deregulation of the homeobox transcription factor gene DUX4 , which is reported in 4–7% of childhood B-ALL cases [ 225 ]. It was indicated that the DUX4 rearrangement is a clonal event acquired in the early stage of leukemogenesis [ 226 ].…”
Section: Genetic Biomarkersmentioning
confidence: 99%
“…DUX4 is present in the D4Z4 repeats of the subtelomeric region of chromosome 4q or the homologous region at 10q. However, D4Z4 repeats go through the process of insertion to the IGH locus on chromosome 14 [ 225 , 228 ]. This rearrangement leads to disruption of the highly conserved C terminus of DUX4 , which is necessary for the process of DUX4 oncogenic activation.…”
Section: Genetic Biomarkersmentioning
confidence: 99%
“…Additionally, AYA patients presented longer disease-free survival after complete remission (CR) [ 229 ]. In the context of applied intensive chemotherapy, it appears that DUX4 -r in B-ALL patients presents favorable outcomes [ 225 ]. The differences in prognosis between pediatric and adult patients were highlighted with better outcomes in the first group of patients [ 130 , 219 ].…”
Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.
“…It is also associated with transcriptional deregulation (usually deletion) of ERG and IKZF1 del (63% and 28%, respectively) [58,59]. DUX4 patients tend to be slightly older (median age 9.8 y in Ma-Spore) [60][61][62], with low white cell counts (median 10,000/µL) [60,63,64].…”
Acute lymphoblastic leukemia (ALL) is the most common cancer among children. This aggressive cancer comprises multiple molecular subtypes, each harboring a distinct constellation of somatic, and to a lesser extent, inherited genetic alterations. With recent advances in genomic analyses such as next-generation sequencing techniques, we can now clearly identify >20 different genetic subtypes in ALL. Clinically, identifying these genetic subtypes will better refine risk stratification and determine the optimal intensity of therapy for each patient. Underpinning each genetic subtype are unique clinical and therapeutic characteristics, such as age and presenting white blood cell (WBC) count. More importantly, within each genetic subtype, there is much less variability in treatment response and survival outcomes compared with current risk factors such as National Cancer Institute (NCI) criteria. We review how this new taxonomy of genetic subtypes in childhood ALL interacts with clinical risk factors used widely, i.e., age, presenting WBC, IKZF1del, treatment response, and outcomes.
“…These articles cover significant themes in childhood cancer research and include biological studies on the role of MYCN in poor prognosis Wilms’ tumor [ 1 ] and the mTOR complexes in rhabdomyosarcoma [ 2 ]; studies exploring biologically based treatments in ependymoma [ 3 ] and osteosarcoma [ 4 ]; a comprehensive description of a novel orthotopic model for radiation-induced glioma which will be invaluable for preclinical testing [ 5 ]; and two comprehensive review articles on leukemias. One review describes recently identified rearrangements of DUX4 with IGH in childhood B-cell acute lymphoblastic leukemia (ALL) and the diagnostic challenges associated with identifying the rearrangement [ 6 ], and the second proposes that infant acute myeloid leukemia (AML) is a biologically and clinically distinct entity from AML in older children [ 7 ]. An additional original research article [ 8 ] emphasizes the importance of monitoring for spinal deformities in children with central nervous system (CNS) tumors and the advantages of early assessment and surgical interventions where needed.…”
This small collection of six original research papers and two review articles in the Special Issue “Rare Childhood Malignancy” highlights the diversity and importance of empirical research into childhood malignancy, a theme that underpins the significant advances that have been made in treating the diseases that constitute cancers in children [...]
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