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The MYB gene is a master regulator of hematopoiesis and contributes to leukemogenesis in several species including humans. Although it is clear that MYB can promote proliferation, suppress apoptosis and block differentiation, the identities of the MYB target genes that mediate these effects have only been partially elucidated. Several studies, including our own, have collectively identified substantial numbers of MYB target genes, including candidates for each of these activities; however, functional validation, particularly in the case of differentiation suppression, has lagged well behind. Here we show that GFI1, which encodes an important regulator of hematopoietic stem cell (HSC) function and granulocytic differentiation, is a direct target of MYB in myeloid leukemia cells. Chromatin immunoprecipitation and reporter studies identified a functional MYB-binding site in the promoter region of GFI, whereas ectopic expression and small hairpin RNA-mediated knockdown of MYB resulted in concomitant increases and decreases, respectively, in GFI1 expression. We also demonstrate that GFI1, like MYB, can block the induced monocytic differentiation of a human acute myeloid leukemia cell line, and most importantly, that GFI1 is essential for MYB's ability to block monocytic differentiation. Thus, we have identified a target of MYB that is a likely mediator of its myeloid differentiation-blocking activity, and which may also be involved in MYB's activities in regulating normal HSC function and myeloid differentiation. [ABSTRACT FROM AUTHOR]

The Myb protein was first identified as an oncogene that causes leukemia in chickens. Since then, it has been widely associated with different types of cancers and studied in detail in myeloid leukemias. However, despite these studies, its role in the induction, pathogenesis and maintenance of AML, and other blood disorders, is still not well understood. Recent efforts to uncover its plethora of transcriptional targets have provided key insights into understanding its mechanism of action. This review evaluates our current knowledge of the role of Myb in leukemia, with a particular focus on AML, from the vast literature spanning three decades, highlighting key studies that have influenced our understanding. We discuss recent insights into its role in leukemogenesis and how these could be exploited for the therapeutic targeting of Myb, its associated co-regulators or its target genes, in order to improve outcomes in the treatment of a wide range of hematopoietic malignancies. [ABSTRACT FROM AUTHOR]

Background: PG545 is a heparan sulfate (HS) mimetic that inhibits tumour angiogenesis by sequestering angiogenic growth factors in the extracellular matrix (ECM), thus limiting subsequent binding to receptors. Importantly, PG545 also inhibits heparanase, the only endoglycosidase which cleaves HS chains in the ECM. The aim of the study was to assess PG545 in various solid tumour and metastasis models.Methods: The anti-angiogenic, anti-tumour and anti-metastatic properties of PG545 were assessed using in vivo angiogenesis, solid tumour and metastasis models. Pharmacokinetic (PK) data were also generated in tumour-bearing mice to gain an understanding of optimal dosing schedules and regimens.Results: PG545 was shown to inhibit angiogenesis in vivo and induce anti-tumour or anti-metastatic effects in murine models of breast, prostate, liver, lung, colon, head and neck cancers and melanoma. Enhanced anti-tumour activity was also noted when used in combination with sorafenib in a liver cancer model. PK data revealed that the half-life of PG545 was relatively long, with pharmacologically relevant concentrations of radiolabeled PG545 observed in liver tumours.Conclusion: PG545 is a new anti-angiogenic clinical candidate for cancer therapy. The anti-metastatic property of PG545, likely due to the inhibition of heparanase, may prove to be a critical attribute as the compound enters phase I clinical trials. [ABSTRACT FROM AUTHOR]

c-Myb is an essential hematopoietic transcription factor that controls proliferation and differentiation of progenitors during blood cell development. Whereas sumoylation of the C-terminal regulatory domain (CRD) is known to have a major impact on the activity of c-Myb, no role for noncovalent binding of small ubiquitin-like modifier (SUMO) to c-Myb has been described. Based on the consensus SUMO-interacting motif (SIM), we identified and examined putative SIMs in human c-Myb. Interaction and reporter assays showed that the SIM in the in the transactivation domain of c-Myb (V267NIV) is functional. This motif is necessary for c-Myb to be able to interact noncovalently with SUMO, preferentially SUMO2/3. Destroying the SUMO-binding properties by mutation resulted in a large increase in the transactivation potential of c-Myb. Mutational analysis and overexpression of conjugation-defective SUMO argued against intramolecular repression caused by sumoylated CRD and in favor of SUMO-dependent repression in trans. Using both a myeloid cell line-based assay and a primary hematopoietic cell assay, we addressed the transforming abilities of SUMO binding and conjugation mutants. Interestingly, only loss of SUMO binding, and not SUMO conjugation, enhanced the myeloid transformational potential of c-Myb. c-Myb with the SIM mutated conferred a higher proliferative ability than the wild-type and caused an effective differentiation block. This establishes SUMO binding as a mechanism involved in modulating the transactivation activity of c-Myb, and responsible for keeping the transforming potential of the oncoprotein in check. [ABSTRACT FROM AUTHOR]

Aberrant Wnt signaling mediated by mutations affecting APC (adenomatous polyposis coli) or β-catenin initiates the majority of human colorectal cancers (CRC) and drives tumorigenesis through the activation of specific genes such as MYC. We report here a novel association whereby another oncogenic transcription factor, MYB/c-Myb, is necessary for intestinal adenoma development directed by activated Wnt signaling. APCMin/+ mice in which c-myb is haploinsufficient survive longer than wild-type APCMin/+ animals due to a delay in adenoma formation. Intestinal adenomas from APCMin/+ mice were assessed and found to have high levels of c-myc gene expression. We explored the relationship between activated Wnt signaling and MYB in regulating MYC and found activated β-catenin in combination with MYB induces robust upregulation of MYC promoter activity, as well as endogenous MYC mRNA and protein expression, in human cells. This cooperation occurred through independent binding of MYB and β-catenin to the MYC promoter. These data highlight a cooperative function for MYB in the context of activated Wnt signaling and provide a molecular basis for the expression of MYC in CRC. [ABSTRACT FROM AUTHOR]

The tumor suppressor Gadd45α was earlier shown to be a repressed target of sustained receptor-mediated ERK1/2 signaling. We have identified Gadd45α as a downregulated gene in response to constitutive signaling from two FLT3 mutants (FLT3-ITD and FLT3-TKD) commonly found in AML, and a leukemogenic GM-CSF receptor trans-membrane mutant (GMR-V449E). GADD45A mRNA downregulation is also associated with FLT3-ITD+ AML. Sustained ERK1/2 signaling contributes significantly to receptor-mediated downregulation of Gadd45α mRNA in FDB1 cells expressing activated receptor mutants, and in the FLT3-ITD+ cell line MV4;11. Knockdown of Gadd45α with shRNA led to increased growth and survival of FDB1 cells and enforced expression of Gadd45α in FDB1 cells expressing FLT3-ITD or GMR-V449E resulted in reduced growth and viability. Gadd45α overexpression in FLT3-ITD+ AML cell lines also resulted in reduced growth associated with increased apoptosis and G1/S cell cycle arrest. Overexpression of Gadd45α in FDB1 cells expressing GMR-V449E was sufficient to induce changes associated with myeloid differentiation suggesting Gadd45α downregulation contributes to the maintenance of receptor-induced myeloid differentiation block. Thus, we show that ERK1/2-mediated downregulation of Gadd45α by sustained receptor signaling contributes to growth, survival and arrested differentiation in AML.Leukemia (2009) 23, 729–738; doi:10.1038/leu.2008.349; published online 8 January 2009 [ABSTRACT FROM AUTHOR]

Although dividing the posterior communicating artery (PComA) during surgery has been criticized for increasing the risk of ischaemia, this procedure increases working space improving visibility and the ability to manipulate during treatment of basilar tip aneurysms via the pterional approach. We divided a hypoplastic PComA in 4 of our cases of basilar tip aneurysm. This was necessary because either (1) the length of the PComA and intracranial internal carotid artery (ICA) limited medial retraction of the ICA and access to the basilar bifurcation region, or (2) the PComA and its perforators ran just in front of the aneurysm, interfering with its exposure. We were able to clip the aneurysm neck in all four patients, three of whom had complications including temporary impairment of consciousness, ocular movement disorders and altered sensation in the extremities. Patients with complications showed transient hypersomnolence immediately after surgery; computed tomography showed small thalamic infarctions. However, in two of three patients the ischaemic events occurred contralateral to the side of PComA section. All patients regained consciousness within a week and were discharged with mild ocular movement palsies. In our cases except one with ischaemic complications, thalamic infarction probably resulted from thalamo-perforating artery injury when the aneurysm neck was clipped, rather than tuberothalamic artery injury due to section of the PComA. Taking previous reports and our results into consideration, we believe that division of a hypoplastic PComA is a safe procedure in particular cases when the grade of subarachnoid haemorrhage is not poor and there are no cerebrovascular risk factors, although we realize it is desirable to preserve normal blood flow. [ABSTRACT FROM AUTHOR]