Disease relevance of YWHAE

• Affected individuals with the hepatocerebral form of MDS have early progressive liver failure and neurological abnormalities, hypoglycemia and increased lactate in body fluids [1].
• The myelodysplastic/myeloproliferative diseases (MDS/MPDs) are a heterogeneous group of myeloid neoplasms that share characteristics with chronic myeloproliferative diseases and myelodysplastic syndromes [2].
• No single gene defect has been firmly associated with MDS/MPDs, and no animal models have been developed for these diseases [2].
• In patients with severe congenital neutropenia (SCN), sepsis mortality is reduced by treatment with granulocyte colony-stimulating factor (G-CSF), but myelodsyplastic syndrome and acute myeloid leukemia (MDS/AML) have been reported [3].
• None of the 344 patients with idiopathic or cyclic neutropenia developed MDS/AML [4].

Psychiatry related information on YWHAE

• While the MDS also suggested a relationship of tamoxifen with a lower prevalence of Alzheimer's disease, there seemed to be an increased prevalence of depression among treated women [5].

High impact information on YWHAE

• We used homozygosity mapping in three kindreds of Druze origin to map the gene causing hepatocerebral MDS to a region of 6.1 cM on chromosome 2p13, between markers D2S291 and D2S2116 [1].
• High frequency of the JAK2 V617F mutation in patients with thrombocytosis (platelet count > 600 x 109/L) and ringed sideroblasts more than 15% considered as MDS/MPD, unclassifiable [6].
• After 10 years, the cumulative incidence was 8% for sepsis mortality and 21% for MDS/AML [3].
• Engraftment of distinct clonal MDS-derived hematopoietic precursors in NOD/SCID-beta2-microglobulin-deficient mice after intramedullary transplantation of hematopoietic and stromal cells [7].
• In addition to the 31 patients who developed MDS/AML, the SCNIR also has data on 9 additional neutropenic patients whose bone marrow studies show cytogenetic clonal changes but the patients are without transformation to MDS/AML [4].

Chemical compound and disease context of YWHAE

• The immunomodulatory drug and thalidomide analogue lenalidomide is currently in late stage clinical development for MDS and multiple myeloma [8].
• Of 1774 patients with breast cancer given mitoxantrone (MTZ) with methotrexate (n = 492) or with methotrexate and mitomycin C (n = 1282), nine developed MDS/AML after a median of 2.5 years [9].
• To evaluate its toxicity and efficacy in a combination regimen with cytarabine, we conducted a clinical phase I/II trial in patients with relapsed acute myeloid leukemia (AML) or relapsed or newly diagnosed MDS RAEB, RAEB-t or CMML [10].
• CONCLUSIONS: According to these findings, the predominant MC type in the bone marrow in neoplastic states such as MDS and mastocytosis is MC(T) (MC expressing only tryptase) [11].
• We diagnosed a probable fludarabine-induced secondary MDS approximately 18 months after treatment of a low grade non-Hodgkin's lymphoma [12].

Biological context of YWHAE

• Assignment of the human 14-3-3 epsilon isoform (YWHAE) to human chromosome 17p13 by in situ hybridization [13].
• The phenomena of IESs and of MDS scrambling represent remarkable flexibility of the hypotrich genome, possibly reflecting a process of MDS shuffling that facilitates the evolution of genes [14].
• In conclusion, genetic predisposition as well as epigenetic events contribute to the etiology of t-AML/MDS [15].
• Also, Dlk1 mRNA was elevated in mononuclear, low density bone marrow cells from 11/38 MDS patients, 5/11 AML M6 and 2/4 AML M7 samples [16].
• Microsatellite analysis confirmed losses of heterozygosity (LOH) affecting the JAK2 region on chromosome 9p in MB-02, MUTZ-8 and UKE-1, but also in HEL, the only JAK2mu cell line lacking any reported MPD/MDS history [17].

Anatomical context of YWHAE

• A similar effect was seen in the lymphocytes of AML/MDS patients during treatment with BAY 43-9006 [18].
• Pharmacodynamic monitoring of BAY 43-9006 (Sorafenib) in phase I clinical trials involving solid tumor and AML/MDS patients, using flow cytometry to monitor activation of the ERK pathway in peripheral blood cells [18].
• We analyzed results of 40 infants less than 2 years of age who received bone marrow transplants (BMT) between May 1974 and January 1995 for treatment of acute myelogenous leukemia (AML; N = 34) or myelodysplastic syndrome (MDS; N = 6) to determine outcome and survival performance [19].
• Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS [20].
• All five JAK2mu cell lines displayed cytogenetic hallmarks of MDS, namely losses of 5q or 7q, remarkably in 4/5 cases affecting both chromosomes [17].

Associations of YWHAE with chemical compounds

• In this article, we describe its application to phase I trials of BAY 43-9006 in solid tumor and AML/MDS patients [18].
• There is also evidence for an association between MMR deficient AML/MDS and immunosuppressive treatment with thiopurine drugs [21].
• Here we review how MMR interacts with alkylating agent and thiopurine-induced DNA damage and suggest possible ways in which MMR defects may arise in therapy-related AML/MDS [21].
• The leukemic transformation in our cases most probably reflects the natural progression of MDS, though it clearly demonstrates that thalidomide is ineffective in controlling blast proliferation in t-MDS [22].
• Twenty-one patients (11 AML, 10 MDS/CMML) entered the study and were treated with 1.25 mg/m2 topotecan as continuous intravenous infusion daily for 5 days and cytarabine 1.0 g/m2 by infusion over 2 h daily for 5 days (TA) [10].

Analytical, diagnostic and therapeutic context of YWHAE

• Therapy-related MDS and AML are complications of intensive chemotherapy regimens [23].
• We have found by real-time RT-PCR that Dlk1 mRNA levels were high in CD34(+) cells in 10 of 12 MDS samples compared with CD34(+) cells from 11 normals [16].
• The results indicate a higher frequency of binucleated micronucleated cells in MDS in respect to the control group (16.1+/-9.1 per thousand versus 8.7+/-5.4 per thousand) [24].
• When the PCR method was used with a group of 40 patients, we also observed a higher sensitivity when BDS samples were examined (80.8% in BDS samples versus 57.7% in MDS samples) [25].
• Prospective cohort study of 28,807 North Carolina Medicare SNF residents aged >65 years with a complete MDS assessment in 1999 [26].

References