Purpose: In childhood acute lymphoblastic leukemia (ALL), f25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood. Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Mu« nster study group. Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern.We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G 2 -M phase cells and this correlated well with the expression level of cell cycle genes. Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes.The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children (1). Although event-free survival rates range between 70% and 75%, relapse of ALL remains the fourth most frequent diagnosis in childhood cancer affecting 25% of ALL patients (2). At relapse, overall cure rates of f40% remain unsatisfactory and survival rates are particularly poor in certain subgroups (3). Treatment of relapse usually implies intensified polychemotherapy containing high-dose elements. Although in most children, second remissions can be induced high-risk patients require further treatment intensification by stem cell transplantation. Stem cell transplantation provides a better relapse-free survival rate than chemotherapy alone but is also associated with higher treatment-related morbidity and mortality rates (2). Thus, alternative treatment strategies are needed to improve the treatment and outcome of patients with relapsed ALL.In the treatment of ALL relapse, intensity of chemotherapy and stem cell transplantation are indicated by well-established prognostic factors (summarized in ref.2), with the most evident being the time to relapse. Early recurrence of disease with respect to frontline therapy affects f60% of patients and is associated with a high rate of nonresponse to treatment, shorter duration of second ...

MYCN amplification drives one in six cases of neuroblastoma. The supernumerary gene copies are commonly found on highly rearranged, extrachromosomal circular DNA. The exact amplicon structure has not been described thus far and the functional relevance of its rearrangements is unknown. Here, we analyzed the MYCN amplicon structure and its chromatin landscape. This revealed two distinct classes of amplicons which explain the regulatory requirements for MYCN overexpression. The first class always co-amplified a proximal enhancer driven by the noradrenergic core regulatory circuit (CRC). The second class of MYCN amplicons was characterized by high structural complexity, lacked key local enhancers, and instead contained distal chromosomal fragments, which harbored CRC-driven enhancers. Thus, ectopic enhancer hijacking can compensate for the loss of local gene regulatory elements and explains a large component of the structural diversity observed in MYCN amplification.

Supplementary Table 1 from Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Supplementary Figure 1 from Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

<div>Abstract<p><b>Purpose:</b> In childhood acute lymphoblastic leukemia (ALL), ∼25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood.</p><p><b>Experimental Design:</b> Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group.</p><p><b>Results:</b> We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G₂-M phase cells and this correlated well with the expression level of cell cycle genes.</p><p><b>Conclusions:</b> Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.</p></div>