Oncogenic activation of tyrosine kinase signaling pathway is recurrent in human leukemia. To gain insight into the oncogenic process leading to acute megakaryoblastic leukemia (AMKL), we performed sequence analyses of a subset of oncogenes known to be activated in human myeloid and myeloproliferative disorders. In a series of human AMKL samples from both Down syndrome and non-Down syndrome patients, mutations were identified within KIT, FLT3, JAK2, JAK3, and MPL genes, with a higher frequency in DS than in non-DS patients. The novel mutations were analyzed using
Long noncoding RNAs (lncRNAs) are pervasively transcribed in the eukaryotic genome [1] and are important for the control of master regulatory genes that are involved in cell differentiation and development [2, 3]. Here, we show that a 5' UTR-overlapping lncRNA regulates the male-specific expression of the DM-domain gene doublesex1 (dsx1) in the crustacean Daphnia magna, which produces males in response to environmental stimuli. This lncRNA, named doublesex1 alpha promoter-associated long RNA (DAPALR), is transcribed upstream the transcription start site (TSS) in a sense orientation and subjected to 5' end capping and 3' end processing at a stem-loop structure before the dsx1 coding exon. Similar to dsx1, its expression is only activated in males by the juvenile hormone (JH) and basic-leucine zipper (bZIP) transcription factor Vrille (Vri) and is maintained during embryogenesis. Knockdown of DAPALR in males silenced dsx1 and led to feminization, including egg production, whereas ectopic expression of DAPALR in dsx1-silenced females resulted in the de-repression of dsx1. We further demonstrate that the DAPALR transcript overlaps the dsx1 5'-UTR, and this overlapping region is required for dsx1 activation. Our results suggest that DAPALR can transactivate and possibly maintain dsx1 expression. This might be important for converting transient environmental signals into stable male development, controlled by the continuous expression of dsx1.
POU1F1, a pituitary-specific POU-homeo domain transcription factor, plays an essential role in the specification of the somatotroph, lactotroph and thyrotroph lineages and in the activation of GH1, PRL and TSHβ transcription. Individuals with mutations in POU1F1 present with combined deficiency of GH, PRL and TSH. Here, we identified a heterozygous missense mutation with evidence of pathogenicity, at the POU1F1 locus, in a large family in which an isolated growth hormone deficiency segregates as an autosomal dominant trait. The corresponding p.Pro76Leu mutation maps to a conserved site within the POU1F1 transactivation domain. Bandshift assays revealed that the mutation alters wild-type POU1F1 binding to cognate sites within the hGH-LCR and hGH1 promoter, but not to sites within the PRL promoter, and it selectively increases binding affinity to sites within the hGH-LCR. Co-immunoprecipitation studies reveal that this substitution enhances interactions of POU1F1 with three of its cofactors, PITX1, LHX3a and ELK1, and that residue 76 plays a critical role in these interactions. The insertion of the mutation at the mouse Pou1f1 locus results in a dramatic loss of protein expression despite normal mRNA concentrations. Mice heterozygous for the p.Pro76Leu mutation were phenotypically normal while homozygotes demonstrated a dwarf phenotype. Overall, this study unveils the involvement of POU1F1 in dominantly inherited isolated GH deficiency and demonstrates a significant impact of the Pro76Leu mutation on DNA-binding activities, alterations in transactivating functions and interactions with cofactors. Our data further highlight difficulties in modeling human genetic disorders in the mouse despite apparent conservation of gene expression pathways and physiologic functions.
Induction by gamma interferon (IFN-,y) of the gene encoding the human high-affinity Fcy receptor (FcyRl) in myeloid cells requires an IFN--y response region (GRR) and a myeloid cell-activating transcription element (MATE). GRR and MATE interact with factors to form, respectively, an IFN--y-activating complex (GIRE-BP), depending on the phosphorylation of the 91-kDa protein (subunit of ISGF3), and a cell-type-specific complex (MATE-BP Our approach to characterization of lineage-specific transcription factors was to study the mechanisms of expression of a lineage-specific marker gene such as the gamma interferon (IFN--y)-induced gene encoding the human high-affinity receptor for immunoglobulin G (Fc-yRl) (1). Studies of its promoter led to the identification of two cis-DNA elements, IFN-y responsive region (GRR) (2, 28) and myeloid cell-activating transcription element (MATE) (31), involved, respectively, in its IFN-y-induced and myeloid cell-restricted expression.The GRR motif is a target for proteins forming an IFN-oa-or IFN--y-activated complex, 31,49). At least, one IFN regulatory factor, the 91-kDa protein (7,17,21), was identified as a component of 29,31). Tyrosine phosphorylation of this factor and of two other factors of 113 and 84 kDa (37) depends on the activation of Tyk2 (46) and JAK1 (23) following binding of IFN-at to its cell surface receptor. After translocation to the nucleus (17), these factors are found to be associated with a 48-kDa DNA-binding protein (21) targeting the IFN-stimulated response element (ISRE) to form a complex referred to as ISGF3 (7). Although GIRE-BP
This study of the first nonconsanguineous patient with LHX3 mutations demonstrates the pleiotropic roles of LHX3 during development and its full involvement in the complex disease phenotype. Isolated limitation of head rotation may exist in heterozygous carriers and would result from a dominant-negative effect. These data allowed the first prenatal diagnoses of this severe condition to be performed.
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