Loss of a whole chromosome 5 or a deletion of the long arm of chromosome 5, ؊5/del(5q), is a recurring abnormality in myeloid neoplasms. The APC gene is located at chromosome band 5q23, and is deleted in more than 95% of patients with a ؊5/del(5q), raising the question of whether haploinsufficiency of APC contributes to the development of myeloid neoplasms with loss of 5q. We show that conditional inactivation of a single allele IntroductionMyelodysplastic syndromes (MDSs) are a group of heterogeneous disorders of hematopoietic stem cells (HSCs) characterized by blood cytopenias due to ineffective hematopoiesis. 1 Approximately 30% to 40% of primary MDS transforms to acute myeloid leukemia (AML). 1 MDS can arise de novo or as a result of previous cytotoxic therapy (t-MDS), including chemotherapy, radiation therapy, and immunosuppressive therapy. Recurring karyotypic abnormalities, including Ϫ5/ del(5q), Ϫ7/del(7q), ϩ8, and del(20q), have been identified in approximately 50% of patients with a primary MDS. 2,3 Loss of a whole chromosome 5 or a del(5q) are among the most common recurring cytogenetic abnormalities, and are noted in approximately 10% to 15% of patients with primary MDS or AML de novo, and in more than 40% of patients with t-MDS/t-AML. 2,4 MDS with an isolated del(5q) (formerly termed the 5qϪ syndrome) is a distinct subtype of MDS, characterized by macrocytosis, anemia, and a low rate of leukemic transformation. 5 In contrast, the advanced stages of MDS, AML de novo, or t-MDS/t-AML with Ϫ5/del(5q) are characterized by complex karyotypes, a poor prognosis, and relative resistance to conventional therapies. 4,6,7 These features suggest that additional acquired genetic alterations occur in the advanced stages of MDS or t-MDS/t-AML, accelerating the progression of the disease.Two commonly deleted segments (CDSs) within 5q33.1 and 5q31 have been identified by cytogenetic analysis of MDS with an isolated del(5q) (5q33.1), or MDS, AML de novo, and t-MDS/t-AML with a del(5q) (5q31). 8,9 Thus far, biallelic deletions or inactivating mutations have been not reported in genes located in the 5q CDSs [8][9][10] The existing data support a haploinsufficiency model, in which loss of a single allele of 1 or more genes on 5q contributes to the pathogenesis of MDS or t-MDS/t-AML with a Ϫ5/del(5q). 10,11 A number of genes located on 5q, including RPS14, 12 EGR1, 13 NPM1, 14 and CTNNA1, 15 have been implicated in the development of myeloid disorders due to a gene dosage effect.The APC tumor suppressor gene is located at chromosome band 5q23, and loss of a single allele of APC occurs in more than 95% of patients with myeloid neoplasms and Ϫ5/del(5q). Loss of function of APC is responsible for the initiation and progression of colorectal cancer. 16 APC, a multifunctional protein, is involved in the regulation of the Wnt signaling pathway via its ability to control the degradation of ␤-catenin. 16 Other cellular processes in which APC plays a role include cell migration, cell adhesion, spindle assembly, and chromosome seg...

• Egr1 haploinsufficiency in cooperation with reduced Tp53 activity accelerates the development of hematologic disease in mice.• Loss of 1 copy of Egr1 and Apc in hematopoietic stem cells, in cooperation with Tp53 loss, results in myeloid neoplasms.An interstitial deletion of chromosome 5, del(5q), is the most common structural abnormality in primary myelodysplastic syndromes (MDS) and therapy-related myeloid neoplasms (t-MNs) after cytotoxic therapy. Loss of TP53 activity, through mutation or deletion, is highly associated with t-MNs with a del(5q). We previously demonstrated that haploinsufficiency of Egr1 and Apc, 2 genes lost in the 5q deletion, are key players in the progression of MDS with a del(5q). Using genetically engineered mice, we now show that reduction or loss of Tp53 expression, in combination with Egr1 haploinsufficiency, increased the rate of development of hematologic neoplasms and influenced the disease spectrum, but did not lead to overt myeloid leukemia, suggesting that altered function of additional gene(s) on 5q are likely required for myeloid leukemia development. Next, we demonstrated that cell intrinsic loss of Tp53 in hematopoietic stem and progenitor cells haploinsufficient for both Egr1 and Apc led to the development of acute myeloid leukemia (AML) in 17% of mice. The long latency (234-299 days) and clonal chromosomal abnormalities in the AMLs suggest that additional genetic changes may be required for full transformation. Thus, loss of Tp53 activity in cooperation with Egr1 and Apc haploinsufficiency creates an environment that is permissive for malignant transformation and the development of AML. (Blood. 2014;123(7):1069-1078)

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There is accumulating evidence that functional alteration(s) of the bone marrow (BM) microenvironment contribute to the development of some myeloid disorders, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). In addition to a cell-intrinsic role of WNT activation in leukemia stem cells, WNT activation in the BM niche is also thought to contribute to the pathogenesis of MDS and AML. We previously showed that the -haploinsufficient mice ( ) model MDS induced by an aberrant BM microenvironment. We sought to determine whether Apc, a multifunctional protein and key negative regulator of the canonical β-catenin (Ctnnb1)/WNT-signaling pathway, mediates this disease through modulating WNT signaling, and whether inhibition of WNT signaling prevents the development of MDS in mice. Here, we demonstrate that loss of 1 copy of is sufficient to prevent the development of MDS in mice and that altered canonical WNT signaling in the microenvironment is responsible for the disease. Furthermore, the US Food and Drug Administration (FDA)-approved drug pyrvinium delays and/or inhibits disease in mice, even when it is administered after the presentation of anemia. Other groups have observed increased nuclear CTNNB1 in stromal cells from a high frequency of MDS/AML patients, a finding that together with our results highlights a potential new strategy for treating some myeloid disorders.

Salidroside (SAL) is a phenylethanoid glycoside isolated from the medicinal plant Rhodiola rosea. R. rosea has been reported to have beneficial effects on diabetic nephropathy (DN) and high-glucose (HG)-induced mesangial cell proliferation. Given the importance of caveolin-1 (Cav-1) in transcytosis of albumin across the endothelial barrier, the present study was designed to elucidate whether SAL could inhibit Cav-1 phosphorylation and reduce the albumin transcytosis across glomerular endothelial cells (GECs) to alleviate diabetic albuminuria as well as to explore its upstream signaling pathway. To assess the therapeutic potential of SAL and the mechanisms involved in DN albuminuria, we orally administered SAL to db/db mice, and the effect of SAL on the albuminuria was measured. The albumin transcytosis across GECs was explored in a newly established in vitro cellular model. The ratio of albumin to creatinine was significantly reduced upon SAL treatment in db/db mice. SAL decreased the albumin transcytosis across GECs in both normoglycemic and hyperglycemic conditions. SAL reversed the HG-induced downregulation of AMP-activated protein kinase and upregulation of Src kinase and blocked the upregulation Cav-1 phosphorylation. Meanwhile, SAL decreased mitochondrial superoxide anion production and moderately depolarized mitochondrial membrane potential. We conclude that SAL exerts its proteinuria-alleviating effects by downregulation of Cav-1 phosphorylation and inhibition of albumin transcytosis across GECs. These studies provide the first evidence of interference with albumin transcytosis across GECs as a novel approach to the treatment of diabetic albuminuria.

ABSTRACT

Articles you may be interested inAutodetachment spectroscopy and dynamics of dipole bound states of negative ions: 2 A 1-2 B 1 transitions of H2CCC− Long range potential of the A1∑+ u state of Na2 using modulated gain spectroscopy AIP Conf.Rotation-vibration levels in the energy region near the HCP↔HPC X 1 ⌺ ϩ isomerization barrier ͑i.e., the HPC geometry͒ were observed by HCP à -X and C -X stimulated emission pumping ͑SEP͒ spectroscopy. Unlike HCN↔HNC, where the unstable isomer corresponds to a local minimum on the potential energy surface, the HPC isomer corresponds to a saddle point. In the à -X SEP spectra, the lϭ0 and 2 components of pure bend overtone levels ͑0,26рv 2 р42,0͒ and the bend-CP stretch combination levels, ͑0,24,1͒ and ͑0,26,1͒, were sampled. On the other hand, in the C -X SEP spectra, which sample lϭ0 components exclusively, 2 2 :1 3 polyads were identified. These polyads appeared in the SEP spectra as a regular, easily recognizable pattern. Since the C -X SEP spectra appeared to be almost totally Franck-Condon nonselective ͑a large fraction of the predicted total density of lϭ0 levels was observed͒, the polyad pattern was the key to vibrational assignments of highly excited vibrational levels. It was found that the bending vibration exhibits very regular ͑Morse-type͒ behavior up to at least v 2 ϭ42. However, an abrupt change was found in the v 2 -dependence of all of the vibrational fine structure constants above v 2 ϭ36, E ͑0,36,0͒ ϭ22 048 cm Ϫ1 . In addition, a sudden turning on of perturbations in the pure bend overtone levels was also observed to occur at v 2 ϭ32. These abrupt changes in the level structure could be related to an abrupt change in curvature of the potential energy surface along directions perpendicular to the bending coordinate when the bending coordinate is far from equilibrium.

Therapy-related myeloid neoplasm (t-MN) is a distinctive clinical syndrome occurring after exposure to chemotherapy or radiotherapy. t-MN arises in most cases from a multipotential hematopoietic stem cell or, less commonly, in a lineage committed progenitor cell. The prognosis for patients with t-MN is poor, as current forms of therapy are largely ineffective. Cytogenetic analysis, molecular analysis and gene expression profiling analysis of t-MN has revealed that there are distinct subtypes of the disease; however, our understanding of the genetic basis of t-MN is incomplete. Elucidating the genetic pathways and molecular networks that are perturbed in t-MNs, may facilitate the identification of therapeutic targets that can be exploited for the development of urgently-needed targeted therapies.