Evi-1 is a zinc-finger transcriptional factor whose inappropriate expression leads to leukemic transformation in mice and humans. Recently, it has been shown that Evi-1 regulates proliferation of hematopoietic stem/progenitor cells at embryonic stage via GATA-2 up-regulation; however, detailed mechanisms underlying Evi-1-mediated early hematopoiesis are not fully understood. We therefore evaluated hematopoietic potential of Evi-1 mutants using a cultivation system of murine para-aortic splanchnopleural (P-Sp) regions, and found that both the first zinc finger domain and the acidic domain were required for Evi-1-mediated hematopoiesis. The hematopoietic potential of Evi-1 mutants was likely to be related to its ability to up-regulate GATA-2 expression. We also showed that the decreased colony forming capacity of Evi-1-deficient P-Sp cells was successfully recovered by inhibition of TGF-b signaling, using ALK5 inhibitor or retroviral transfer of dominant-negative-type Smad3. T he ecotropic viral integration site-1 (Evi-1) gene was first identified as a common locus of retroviral integration in myeloid tumors in AKXD mice.(1) Evi-1 is highly expressed in cases with human acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) as a consequence of chromosomal rearrangements involving 3q26, where Evi-1 is mapped.(2-5) Alterations such as t(2;3)(p15;q26), inv(3)(q21;q26), t(3;3)(q21;q26), t(3;7)(q27;q22), t(3;12)(q26;p13), t(3;13)(q26; p13-14), and t(3;17)(q26;q22) are representative, but there are some cases with Evi-1 deregulation without any 3q26 rearrangements.(6) The most frequent ones are inv(3)(q21;q26) and t(3;3)(q21;q26), and cases with these two anomalies have elevated platelet counts, marked hyperplasia with dysplastic megakaryocytes, and poor prognosis, which are characterized as 3q21q26 syndrome.(7) These findings indicate that Evi-1 plays a critical role in human leukemogenesis.The alternative forms generated from Evi-1 gene encode two distinct proteins, Evi-1a and Evi-1c, with the latter also called MDS1-Evi-1.(8) Structurally in Evi-1c, amino(N)-terminally to the Evi-1a moiety lies a 188 amino-acid region of homology called the PR domain. The PR domain (PRDI-BF1-RIZ1 homologous domain) has been found in at least 17 kinds of diverse proteins to date, and a large body of evidence suggests that the PR-containing forms contribute to tumor suppression, while the PR-absent forms are oncogenic.(9-12) Consistent with this principle, it has been shown clinically that the expression of Evi-1a (PR-absent form) is associated with highly aggressive AML, but that of Evi-1c (PR-containing form) is not. (13,14) As all PR domain proteins, Evi-1 contains several zinc-finger motifs which are grouped in the first zinc-finger domain (seven motifs) and the second zinc-finger domain (three motifs). Between these two zinc-finger domains, there is a proline-rich repression domain and at the C-terminus there is a highly acidic stretch. (15) We have revealed that Evi-1 possesses diverse functions as an oncoprotein. Evi-1 a...
Intrathymic development of CD4/CD8 double-negative (DN) thymocytes can be tracked by well-defined chronological subsets of thymocytes, and is an ideal target of gene expression profiling analysis to clarify the genetic basis of mature T cell production, by which differentiation of immature thymocytes is investigated in terms of gene expression profiles. In this study, we show that development of murine DN thymocytes is predominantly regulated by largely repressive rather than inductive activities of transcriptions, where lineage-promiscuous gene expression in immature thymocytes is down-regulated during their differentiation. Functional mapping of genes showing common temporal expression profiles implicates previously uncharacterized gene regulations that may be relevant to early thymocytes development. A small minority of genes is transiently expressed in the CD44lowCD25+ subset of DN thymocytes, from which we identified a novel homeobox gene, Duxl, whose expression is up-regulated by Runx1. Duxl promotes the transition from CD44highCD25+ to CD44lowCD25+ in DN thymocytes, while constitutive expression of Duxl inhibits expression of TCR β-chains and leads to impaired β selection and greatly reduced production of CD4/CD8 double-positive thymocytes, indicating its critical roles in DN thymocyte development.
RUNX1 is essential for definitive hematopoiesis and T-cell differentiation. It has beenshown that RUNX1 is phosphorylated at specific serine and threonine residues by several kinase families. However, it remains unclear whether RUNX1 phosphorylation is absolutely required for its biological functions. Here, we evaluated hematopoietic activities of RUNX1 mutants with serine (S)/threonine (T) to alanine (A), aspartic acid (D), or glutamic acid (E) mutations at phosphorylation sites using primary culture systems. Consistent with the results of knockin mice, RUNX1-2A, carrying two phospho-deficient mutations at S276 and S293, retained hematopoietic activity. RUNX1-4A, carrying four mutations at S276, S293, T300, and S303, showed impaired T-cell differentiation activity, but retained the ability to rescue the defective early hematopoiesis of Runx1-deficient cells. Notably, RUNX1-5A, carrying five mutations at S276, S293, T300, S303, and S462, completely lost its hematopoietic activity. In contrast, the phospho-mimic proteins RUNX1-4D/E and RUNX1-5D/E exhibited normal function. Our study identifies multiple phosphorylation sites that are indispensable for RUNX1 activity in hematopoiesis. Keywords: Hematopoiesis · Phosphorylation · Posttranslational modification · RUNX1 · T-cell differentiation Supporting Information available online IntroductionRUNX1 is a key hematopoietic transcription factor and is a frequent target of leukemia-related chromosomal translocations Correspondence: Dr. Mayumi Yoshimi e-mail: kurokawa-tky@umin.ac.jp [1][2][3]. Genetic studies have revealed an essential role of RUNX1 in definitive hematopoiesis and thymocyte development [4][5][6]. We have developed several culture systems to replicate the hematopoietic defects of Runx1-deficient mice, which enable easy evaluation of the physiological functions of RUNX proteins [7,8].It has been shown that RUNX1 phosphorylated at specific serine (S) and threonine (T) residues controls both transcriptional activity and protein stability. Extracellular signal-regulated kinase (ERK) phosphorylates RUNX1 at S276 and S293, and itwww.eji-journal.eu Eur. J. Immunol. 2012. 42: 1044-1050 Molecular immunology 1045 increases transactivation potency by preventing interaction with the mSin3A corepressor [9,10]. In addition to these residues, we also identified three residues, T300, S303, and S462, as targets of ERK-mediated phosphorylation upon stimulation with phorbol ester [11]. RUNX1 is also phosphorylated by homeodomaininteracting protein kinase 2 (HIPK2) [12] and cyclin-dependent kinases (CDKs) [13][14][15]. However, the predicted RUNX1 activation by phosphorylation was challenged by a recent report using knockin mouse models. Unexpectedly, mice expressing mutant RUNX1 protein that harbors phospho-deficient mutations at either S276/S293 or S276/S303 are phenotypically normal [16]. Thus, it remains unclear whether RUNX1 phosphorylation is absolutely required for its function.To address this issue, we evaluated the hematopoietic activities of various phospho-deficie...
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Spermatic cord lymphoma is a rare lethal disease. It has a poor prognosis even in stage I or II disease when treated locally, therefore, multidisciplinary treatment for early stage is recommended. On the other hand, the treatment of choice for stage III or IV spermatic cord lymphoma remains to be determined. It is said that spermatic cord lymphoma is clinicopathologically similar to primary testicular lymphoma, therefore the treatment of spermatic cord lymphoma has often been determined by reference to the recommended treatment for primary testicular lymphoma. Here we report a new case of spermatic cord lymphoma, which was found in stage IV disease. We also review thirty-three cases which have been reported as spermatic cord lymphoma to date, and discuss treatment options.
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