Letters to the Editor haematologica/the hematology journal | 2007; 92(10) | 1435 | cAMP response element binding protein (CREB) overexpression CREB has been described as critical for leukemia progression CREB has been described as critical for leukemia progress. We investigated CREB expression in ALL and AML pediatric patients. CREB protein was significantly high (p<0.001) at diagnosis but not during remission. This study underlines the role of CREB in leukemia and suggests new insights into the transformation process. Haematologica 2007; 92:1435 92: -1437 Acute leukemia accounts for about one third of childhood cancers.1 Recent advances in functional genomics has highlighted the need to investigate complex gene expression patterns to discover novel signaling and disease-related pathways.2 CREB is a transcription factor that regulates gene expression principally through activation of the cyclic AMP (cAMP)-dependent cell signal transduction pathways by binding to the cAMP response element (CRE) region at the promoters.3 CREB is phosphorylated in Serine 133 principally by protein kinase A, and this modification enhances its transactivation potential.4 It has been reported to be over expressed in adult myeloid leukemia and to play a role in myeloid transformation and leukemia progression.
5,6We investigated the expression of CREB in childhood acute leukemia. We analyzed a total of 86 acute lymphoid (ALL), 40 acute myeloid (AML) leukemia patients (Table 1) and a series of leukemia cell lines to reveal the potential role of this signaling pathway in leukemogenesis. CREB expression was also studied in samples collected from 86 ALL and 21 AML patients during remission to establish a correlation with the disease stage. As control group we used bone marrow (BM) samples from 19 patients affected by other nonneoplastic hematologic disorders (diagnoses: neutropenia, n=4; thrombocytopenia, n=9; anemia, n=3; lymphoma, without BM infiltration n=3) and from 9 healthy donors (7 pediatric and 2 adult samples collected in the process of transplants).Western blot (WB) analysis showed CREB protein overexpression in all leukemia cell lines but not in sorted normal hematopoietic stem cells ( Figure 1A). WB analysis showed CREB overexpressed in 29 out of the 31 (94%) patients with ALL (20/23 with B-lineage ALL; and 7/8 with T-ALL) and in 13 out of 17 (76%) with AML. In addition, CREB resulted in the active form (pCREB) at diagnosis. On the contrary, CREB was not detected in any remission samples or in the control group. Interestingly, CREB expression in samples collected from diagnosis to treatment completion showed a clear correlation with the disease stage ( Figure 1B). To define CREB protein level, a competitive ELISA assay was performed on 16 ALL and 7 AML patients previously analyzed by WB as well as in 55 new ALL and 23 AML patients collected during the study. Average CREB concentration was 151.5 ng/mL in ALL at diagnosis (n=71), and 72 ng/mL in AML at diagnosis (n=30). The distribution of CREB level was significantly lower in A...