SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression

Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri-methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL

Pediatric High Risk Leukemia — Molecular Insights

Acute leukemia comprises of 31% of all cancers in children making it the most common childhood malignancy. Significant strides have been made in treatment, partly through risk stratification and intensified therapy. A number of subtypes remain at high risk for relapse and poor outcome, despite current therapies. Here we describe risk stratification and molecular diagnosis used to identify high risk leukemias and guide treatment. Specific cytogenetic alterations that contribute to high risk B and T cell acute lymphoblastic leukemia (ALL), as well as infant leukemia are discussed. Particular attention is given to genetic alterations in IKZF1, CRLF2, and JAK, that have been identified by whole genome sequencing and recently associated with Ph-like ALL. Ongoing studies of disease mechanisms and challenges in developing pre-clinical patient-derived xenograft models to evaluate therapies are discussed

Genetically engineered mouse models of human B-cell precursor leukemias

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Non-Commercial License.B-cell precursor acute lymphoblastic leukemias (pB-ALLs) are the most frequent type of malignancies of the childhood, and also affect an important proportion of adult patients. In spite of their apparent homogeneity, pB-ALL comprises a group of diseases very different both clinically and pathologically, and with very diverse outcomes as a consequence of their biology, and underlying molecular alterations. Their understanding (as a prerequisite for their cure) will require a sustained multidisciplinary effort from professionals coming from many different fields. Among all the available tools for pB-ALL research, the use of animal models stands, as of today, as the most powerful approach, not only for the understanding of the origin and evolution of the disease, but also for the development of new therapies. In this review we go over the most relevant (historically, technically or biologically) genetically engineered mouse models (GEMMs) of human pB-ALLs that have been generated over the last 20 years. Our final aim is to outline the most relevant guidelines that should be followed to generate an “ideal” animal model that could become a standard for the study of human pB-ALL leukemia, and which could be shared among research groups and drug development companies in order to unify criteria for studies like drug testing, analysis of the influence of environmental risk factors, or studying the role of both low-penetrance mutations and cancer susceptibility alterations.This work was supported by the German “Bundesamt fur Strah-lenschutz (BfS)” pilot project on childhood leukemia no. 3612S70029. JH has been supported by the German Children’s Cancer Foundation and from the “Forschungskommission” of the medical faculty of the Heinrich Heine University and the “Strategischer Forschungsfond” of the Heinrich-Heine-University. AB has been supported by the German Children’s Cancer Foundation and the Federal Ministry of Education and Research, Bonn, Germany. Research in ISG group is partially supported by FEDER and by MICINN (SAF2012-32810), by NIH grant (R01 CA109335-04A1), by Junta de Castilla y León (BIO/SA06/13) and by the ARIMMORA project (FP7-ENV-2011, European Union Seventh Framework Program). ISG lab is a member of the EuroSyStem and the DECIDE Network funded by the European Union under the FP7 program. Research at CC’s lab was partially supported by FEDER, Fondo de Investigaciones Sanitarias (PI13/00160), CSIC P.I.E., Junta de Castilla y León, and from an institutional grant from the Fundación Ramón Areces.Peer Reviewe

NF-kappa B mediated Up-regulation of CCCTC-binding factor in pediatric acute lymphoblastic leukemia

BACKGROUND: Acute lymphoblastic leukemia (ALL) is the most frequently occurring malignant neoplasm in children. Despite advances in treatment and outcomes for ALL patients, the pathogenesis of the disease remains unclear. Microarray analysis of samples from 100 Chinese children with ALL revealed the up-regulation of CTCF (CCCTC binding factor). CTCF is a highly conserved 11-zinc finger protein that is involved in many human cancers; however, the biological function of CTCF in pediatric ALL is unknown. METHODS: The expression patterns of CTCF were evaluated in matched newly diagnosed (ND), complete remission (CR), and relapsed (RE) bone marrow samples from 28 patients. The potential oncogenic mechanism of CTCF and related pathways in leukemogenesis were investigated in leukemia cell lines. RESULTS: We identified significant up-regulation of CTCF in the ND samples. Importantly, the expression of CTCF returned to normal levels after CR but rebounded in the RE samples. In the pre-B ALL cell line Nalm-6, siRNA-mediated silencing of CTCF expression promoted cell apoptosis and reduced cell proliferation; accordingly, over-expression of a cDNA encoding full-length CTCF protected cells from apoptosis and enhanced cell proliferation. Furthermore, inhibition or activation of the nuclear factor-kappa B (NF-κB) pathway resulted in marked variations in the levels of CTCF mRNA and protein in leukemic cells, indicating that CTCF may be involved downstream of the NF-κB pathway. Moreover, inhibition of the NF-κB pathway increased cell apoptosis, which was partially rescued by ectopic over-expression of CTCF, suggesting that CTCF may play a significant role in the anti-apoptotic pathway mediated by NF-κB. CONCLUSIONS: Our results indicate that CTCF serves as both an anti-apoptotic factor and a proliferative factor in leukemic cells. It potentially contributes to leukemogenesis through the NF-κB pathway in pediatric ALL patients

Targeting HOX/PBX dimers in cancer

The HOX and PBX gene families encode transcription factors that have key roles in establishing the identity of cells and tissues in early development. Over the last 20 years it has become apparent that they are also dysregulated in a wide range of solid and haematological malignancies and have a predominantly pro-oncogenic function. A key mode of transcriptional regulation by HOX and PBX proteins is through their interaction as a heterodimer or larger complex that enhances their binding affinity and specificity for DNA, and there is growing evidence that this interaction is a potential therapeutic target in malignancies that include prostate, breast, renal, ovarian and lung cancer, melanoma, myeloma, and acute myeloid leukaemia. This review summarizes the roles of HOX and PBX genes in cancer and assesses the therapeutic potential of HOX/PBX dimer inhibition, including the availability of biomarkers for its application in precision medicine

Nuclear Translocation of Extradenticle Requires homothorax, which Encodes an Extradenticle-Related Homeodomain Protein

AbstractWe show that homothorax (hth) is required for the Hox genes to pattern the body of the fruit fly, Drosophila melanogaster. hth is necessary for the nuclear localization of an essential HOX cofactor, Extradenticle (EXD), and encodes a homeodomain protein that shares extensive identity with the product of Meis1, a murine proto-oncogene. MEIS1 is able to rescue hth mutant phenotypes and can induce the cytoplasmic-to-nuclear translocation of EXD in cell culture and Drosophila embryos. Thus, Meis1 is a murine homolog of hth. MEIS1/HTH also specifically binds to EXD with high affinity in vitro. These data suggest a novel and evolutionarily conserved mechanism for regulating HOX activity in which a direct protein–protein interaction between EXD and HTH results in EXD's nuclear translocation

UNRAVELING MOLECULAR MECHANISMS UNDERLYING MEIS1ONCOGENIC ACTIVITY; POSSIBLE COMPETITION WITH PREP1

Meis1 and Prep1 homeodomain-containing transcription factors are essential for the normal embryonic development of several tissues and organs. Although they both can recruit Pbx at least for some of their biological function using the same homology region, the Meis1-Pbx and Prep1-Pbx complexes bind different DNA sequences and play opposite roles in tumorigenicity. In cancer, Meis1 has been extensively implicated in leukemia and neuroblastoma. Overexpression of Meis1 greatly shortens the latency and affects the penetrance of myeloid leukemia induced by Hox genes retroviral transduction. Furthermore, Meis1 has essential oncogenic function in all human leukemic MLL- translocation. Although, Meis1 is strongly suggested for involvement in human neuroblastoma and glioma, its function in non-hematological malignancies and solid tumors remains poorly defined. In contrast, Prep1 does not accelerate Hox-induced leukemogenesis. In fact heterozygous or homozygous Prep1-deficient mice develop tumors at high frequency. In mice, Prep1 haploinsufficiency causes spontaneous tumor formation and accelerates development of tumors in E\u3bcMyc transgenic mice. In human tumors, PREP1 is absent or downregulated in a large fraction of tumors including lung, breast and colon cancers. Therefore, Prep1 exerts tumor suppressor function in the cell by maintaining genomic stability and hence preventing neoplastic transformation. Here I show that Meis1 is involved in malignant transformation of Prep1-deficient MEFs and that this can be partially rescued by re-expression of Prep1. I demonstrate that the Pbx-interacting domain of Prep1 is involved in its tumor suppressor function. Moreover, Both Meis1 and Prep1 require Pbx1 for their oncogenic and tumorsppressive functions, respectively. Therefore Meis1 and Prep1 do compete for Pbx1 in the context of tumor development. Furthermore, I find Meis1 interacts with Ddx3x and Ddx5 RNA helicases,which is perturbed in the presence of Prep1. Together, the presented results suggest that Meis1 is a bona-fide oncogene also in non-hematic cells and that Prep1 impairs Meis1 tumorigenicity by either competing for Pbx1 or preventing its interaction with transcriptionally relevant partners

Recognition of Tumor-Specific Proteins in Human Cancer

Cancer is a disease of all ages and even though cancer is not a common disease in younger people, cancer is recognized as one of the most imp0l1ant causes of death at any age. In fact, when considering the main death causes in people younger than thirty years, cancer is second only to accidents. Beyond the age of thirty years, the number of deaths from cancer increases upon aging, gradually at first, rising simply later on. Apm1 from cancer causing death, the disease is fem'ed because patients who suffer from cancer are often condemned to a long and painful terminal illness. Based on their frequency of occurrence, cancers are traditionally categorized as either epithelial cancers (approximately 85% of all human cancers) or non-epithelial cancers (approximately 15% of all human cancers). Cancers arising from epithelial cells (i.e. cells lining the body cavities and skin) are called cm'Cinomas (Latin: km'kinos - crab or lobster; oma - swelling), while those arising from non-epithelial cells are further subdivided according to the tissue and cell type from which they originate. Thus, sarcomas are derived from connective tissue or muscle cells (Greek: sarx - meat), while leukemias are derived from hematopoietic cells (Greek: leucos - white; haimablood). Other non-epithelial cancers include the ones deJived fi'Om cells ofthe nervous system and germinal or embryonal cells