CREBBP HAT domain mutations prevail in relapse cases of high hyperdiploid childhood acute lymphoblastic leukemia

• Published in: Leukemia Vol. 26; no. 8; pp. 1797 - 1803
• Main Authors: Inthal, A, Zeitlhofer, P, Zeginigg, M, Morak, M, Grausenburger, R, Fronkova, E, Fahrner, B, Mann, G, Haas, O A, Panzer-Grümayer, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.08.2012; Nature Publishing Group
• Subjects: 631/208/737; 631/67/2332; 631/67/68; 692/699/67/1990/283/2125; Acute lymphoblastic leukemia; Acute lymphocytic leukemia; Adolescent; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Base Sequence; Biological and medical sciences; Bone marrow; Cancer Research; Care and treatment; Child; Child, Preschool; Children; Chromosomes; Copy number; CREB-binding protein; CREB-Binding Protein - genetics; Critical Care Medicine; Cyclic AMP response element-binding protein; Diagnosis; Diseases; DNA Copy Number Variations; Domains; Drug resistance; Female; Gene mutations; Genes; Genetic aspects; Hematologic and hematopoietic diseases; Hematology; Heterozygosity; Histones; Humans; Intensive; Internal Medicine; Kinases; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Loss of Heterozygosity; Lymphatic leukemia; Male; Medical research; Medical sciences; Medicine; Medicine & Public Health; Mutation; Mutation hot spots; Oncology; original-article; Physiological aspects; Ploidies; Precursor Cell Lymphoblastic Leukemia-Lymphoma - diagnosis; Precursor Cell Lymphoblastic Leukemia-Lymphoma - drug therapy; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Protein Structure, Tertiary - genetics; Recurrence; Relapse; Remission; Remission (Medicine); Risk analysis; Risk factors; Subgroups; Treatment Outcome; Czech Republic; Austria; relapse leukemia; childhood ALL; SNP; high hyperdiploid karyotype; Human; Polyploidy; Relapse; CREBBP; Malignant hemopathy; Binding protein; Lymphoproliferative syndrome; Cytogenetics; Genetics; Acute lymphocytic leukemia; Mutation; Child; Transcription factor CREB; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.60

Despite their apparently good prognosis ∼15% of high hyperdiploid (HD) childhood acute lymphoblastic leukemia (ALL) cases relapse. To search for responsible risk factors we determined copy number aberrations as well as copy neutral loss of heterozygosity (LOH) in 13 matched diagnosis and relapse samples and added the data of the only three available cases from the literature. Deletions and copy neutral LOH in 3 and 2 of the 16 cases directed us to the histone-modifying CREB -binding protein ( CREBBP) gene, whose functional impairment is implicated in drug resistance. We therefore screened all samples for mutations in this gene and discovered 9 acquired sequence mutations in 7/16 cases, leading to an overall frequency of somatic CREBBP aberrations in HD ALL relapse cases of 63% that is considerably higher than that of the reported, mainly non-HD ALL (18.3%). Moreover, mutations in HD cases occur almost exclusively in the HAT domain (8/9; 89%). Hot spot mutations are present at diagnosis in 18.8% of relapsing HD ALL cases but in none of 40 respective cases remaining in long-term remission. Thus, the particular high incidence of CREBBP mutations in relapse-prone HD ALL cases could eventually be exploited for refined risk stratification and customized treatment in this genetic subgroup.