Gene expression profiling was performed on 97 cases of infant ALL from Children's Oncology Group Trial P9407. Statistical modeling of an outcome predictor revealed 3 genes highly predictive of event-free survival (EFS), beyond age and MLL status: FLT3, IRX2, and TACC2. Low FLT3 expression was found in a group of infants with excellent outcome (n = 11; 5-year EFS of 100%), whereas differential expression of IRX2 and TACC2 partitioned the remaining infants into 2 groups with significantly different survivals (5-year EFS of 16% vs 64%; P < .001). When infants with MLL-AFF1 were analyzed separately, a 7-gene classifier was developed that split them into 2 distinct groups with significantly different outcomes (5-year EFS of 20% vs 65%; P < .001). In this classifier, elevated expression of NEGR1 was associated with better EFS, whereas IRX2, EPS8, and TPD52 expression were correlated with worse outcome. This classifier also predicted EFS in an independent infant ALL cohort from the Interfant-99 trial. When evaluating expression profiles as a continuous variable relative to patient age, we further identified striking differences in profiles in infants less than or equal to 90 days of age and those more than 90 days of age. These age-related patterns suggest different mechanisms of leukemogenesis and may underlie the differential outcomes historically seen in these age groups.
"Accordingly, we concentrated on actin regulatory proteins downstream of this pathway that may synergize with contractility to affect blebbing. Epidermal growth factor receptor pathway substrate 8 (Eps8) is an actin bundling and capping protein (Disanza et al., 2004, 2006; Hertzog et al., 2010) that plays a critical role in development of the nervous, auditory and reproductive systems (Lie et al., 2009; Menna et al., 2009, 2013; Manor et al., 2011) and its upregulation in cancers correlates with invasivity and poor prognosis (Griffith et al., 2006; Wang et al., 2009; Kang et al., 2012). Eps8 was originally identified as an actin binding protein downstream of the EGF receptor and to regulate actin through a complex with SOS1 and Abi1 (Fazioli et al., 1993; Scita et al., 1999). "
[Show abstract][Hide abstract] ABSTRACT: Within the confines of tissues, cancer cells can use blebs to migrate. Eps8 is an actin bundling and capping protein whose capping activity is inhibited by Erk, a key MAP kinase that is activated by oncogenic signaling. We tested the hypothesis that Eps8 acts as an Erk effector to modulate actin cortex mechanics and thereby mediate bleb-based migration of cancer cells. Cells confined in a non-adhesive environment migrate in the direction of a very large 'leader bleb.' Eps8 bundling activity promotes cortex tension and intracellular pressure to drive leader bleb formation. Eps8 capping and bundling activities act antagonistically to organize actin within leader blebs, and Erk mediates this effect. An Erk biosensor reveals concentrated kinase activity within leader blebs. Bleb contents are trapped by the narrow neck that separates the leader bleb from the cell body. Thus, Erk activity promotes actin bundling by Eps8 to enhance cortex tension and drive the bleb-based migration of cancer cells under non-adhesive confinement.
"Although FLT3 mutations are rare in B-ALL, expression of either wild-type or mutant FLT3 is frequent in MLLrearranged infant B-ALL cases, which have high CNS relapse rates and poor overall survival (Isoyama et al. 2002; Nagayama et al. 2006; Pieters et al. 2007). Furthermore, high expression of wild-type FLT3 correlated with poor survival in infant B-ALL independent of MLL rearrangement status (Kang et al. 2012). The blood–brain barrier prevents normal lymphocytes from entering the CNS, but inflammation associated with infection or autoimmunity allows lymphocytes to breach this barrier (Wilson et al. 2010). "
[Show abstract][Hide abstract] ABSTRACT: During V(D)J recombination of immunoglobulin genes, p53 and nonhomologous end-joining (NHEJ) suppress aberrant rejoining of DNA double-strand breaks induced by recombinase-activating genes (Rags)-1/2, thus maintaining genomic stability and limiting malignant transformation during B-cell development. However, Rag deficiency does not prevent B-cell leukemogenesis in p53/NHEJ mutant mice, revealing that p53 and NHEJ also suppress Rag-independent mechanisms of B-cell leukemogenesis. Using several cytogenomic approaches, we identified a novel class of activating mutations in Fms-like tyrosine kinase 3 (Flt3), a receptor tyrosine kinase important for normal hematopoiesis in Rag/p53/NHEJ triple-mutant (TM) B-cell leukemias. These mutant Flt3 alleles were created by complex genomic rearrangements with Moloney leukemia virus (MuLV)-related endogenous retroviral (ERV) elements, generating ERV-Flt3 fusion genes encoding an N-terminally truncated mutant form of Flt3 (trFlt3) that was transcribed from ERV long terminal repeats. trFlt3 protein lacked most of the Flt3 extracellular domain and induced ligand-independent STAT5 phosphorylation and proliferation of hematopoietic progenitor cells. Furthermore, expression of trFlt3 in p53/NHEJ mutant hematopoietic progenitor cells promoted development of clinically aggressive B-cell leukemia. Thus, repetitive MuLV-related ERV sequences can participate in aberrant end-joining events that promote development of aggressive B-cell leukemia.
Genes & Development 06/2014; 28(11):1179-90. DOI:10.1101/gad.240820.114 · 10.80 Impact Factor
"So far, a somatic mutation (E680K) and two constitutional mutations (S93L and G514E) of TACC3 have been identified in GBM and ovarian cancer, respectively , , . Studies have shown that up-regulation of TACC3 is found in glioblastoma, non-small cell lung cancer (NSCLC) and multiple myeloma , ,  and may contribute to lymphomagenesis , . Gene expression profiling analysis has revealed that TACC3 is up-regulated during the transition of ductal carcinoma in situ to invasive carcinoma of the breast and in ovarian cancer –. "
[Show abstract][Hide abstract] ABSTRACT: The third member of transforming acidic coiled-coil protein (TACC) family, TACC3, has been shown to be an important player in the regulation of centrosome/microtubule dynamics during mitosis and found to be deregulated in a variety of human malignancies. Our previous studies have suggested that TACC3 may be involved in cervical cancer progression and chemoresistance, and its overexpression can induce epithelial-mesenchymal transition (EMT) by activating the phosphatidylinositol 3-kinase (PI3K)/Akt and extracellular signal-regulated protein kinases (ERKs) signal transduction pathways. However, the upstream mechanisms of TACC3-mediated EMT and its functional/clinical importance in human cervical cancer remain elusive. Epidermal growth factor (EGF) has been shown to be a potent inducer of EMT in cervical cancer and associated with tumor invasion and metastasis. In this study, we found that TACC3 is overexpressed in cervical cancer and can be induced upon EGF stimulation. The induction of TACC3 by EGF is dependent on the tyrosine kinase activity of the EGF receptor (EGFR). Intriguingly, depletion of TACC3 abolishes EGF-mediated EMT, suggesting that TACC3 is required for EGF/EGFR-driven EMT process. Moreover, Snail, a key player in EGF-mediated EMT, is found to be correlated with the expression of TACC3 in cervical cancer. Collectively, our study highlights a novel function for TACC3 in EGF-mediated EMT process and suggests that targeting of TACC3 may be an attractive strategy to treat cervical cancers driven by EGF/EGFR signaling pathways.
PLoS ONE 09/2013; 8(8):e70353. DOI:10.1371/journal.pone.0070353 · 3.23 Impact Factor
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