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Attar, Eyal Chai

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Attar

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Eyal Chai

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Attar, Eyal Chai

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2009 - 200912010 - 20132

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Author's Publications: search.filters.isAuthorOfPublication.09e0fa75-947a-45a0-bca4-cd35ada57dcd

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    Differential regulation of myeloid leukemias by the bone marrow microenvironment
    (2013) Krause, Daniela S.; Fulzele, Keertik; Catic, Andre; Sun, Chia Chi; Dombkowski, David; Hurley, Michael P.; Lezeau, Sanon; Attar, Eyal Chai; Wu, Joy Y.; Lin, Herbert; Divieti-Pajevic, Paola; Hasserjian, Robert; Schipani, Ernestina; Van Etten, Richard A.; Scadden, David
    Like their normal hematopoietic stem cell counterparts, leukemia stem cells (LSC) in chronic myelogenous leukemia (CML) and acute myeloid leukemia (AML) are presumed to reside in specific niches in the bone marrow microenvironment (BMM)1, and may be the cause of relapse following chemotherapy.2 Targeting the niche is a novel strategy to eliminate persistent and drug-resistant LSC. CD443,4 and IL-65 have been implicated previously in the LSC niche. Transforming growth factor (TGF)-β1 is released during bone remodeling6 and plays a role in maintenance of CML LSCs7, but a role for TGF-β1 from the BMM has not been defined. Here, we show that alteration of the BMM by osteoblastic cell-specific activation of the parathyroid hormone (PTH) receptor8,9 attenuates BCR-ABL1-induced CML-like myeloproliferative neoplasia (MPN)10 but enhances MLL-AF9-induced AML11 in mouse transplantation models, possibly through opposing effects of increased TGF-β1 on the respective LSC. PTH treatment caused a 15-fold decrease in LSCs in wildtype mice with CML-like MPN, and reduced engraftment of immune deficient mice with primary human CML cells. These results demonstrate that LSC niches in chronic and acute myeloid leukemias are distinct, and suggest that modulation of the BMM by PTH may be a feasible strategy to reduce LSC, a prerequisite for the cure of CML.
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    Identification of RPS14 as a 5q- syndrome gene by RNA interference screen
    (2013) Ebert, Benjamin; Pretz, Jennifer; Bosco, Jocelyn; Chang, Cindy Y.; Tamayo, Pablo; Galili, Naomi; Raza, Azra; Root, David E.; Attar, Eyal Chai; Ellis, Steven R.; Golub, Todd
    Somatic chromosomal deletions in cancer are thought to indicate the location of tumor suppressor genes, whereby complete loss of gene function occurs through biallelic deletion, point mutation, or epigenetic silencing, thus fulfilling Knudson's two-hit hypothesis.1 In many recurrent deletions, however, such biallelic inactivation has not been found. One prominent example is the 5q- syndrome, a subtype of myelodysplastic syndrome (MDS) characterized by a defect in erythroid differentiation.2 Here, we describe an RNA interference (RNAi)-based approach to discovery of the 5q- disease gene. We find that partial loss of function of the ribosomal protein RPS14 phenocopies the disease in normal hematopoietic progenitor cells, and moreover that forced expression of RPS14 rescues the disease phenotype in patient-derived bone marrow cells. In addition, we identified a block in the processing of pre-rRNA in RPS14 deficient cells that is highly analogous to the functional defect in Diamond Blackfan Anemia, linking the molecular pathophysiology of the 5q- syndrome to a congenital bone marrow failure syndrome. These results indicate that the 5q- syndrome is caused by a defect in ribosomal protein function, and suggests that RNAi screening is an effective strategy for identifying causal haploinsufficiency disease genes.
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    Non-Specific Interstitial Pneumonia as the Initial Presentation of Biphenotypic Acute Leukemia: A Case Report
    (Cases Network Ltd, 2009) Mohan, Arun V; Ramnath, Venktesh R.; Patalas, Eva; Attar, Eyal Chai
    Nonspecific interstitial pneumonia has been linked to numerous etiologies including, most recently, haematologic malignancy. We present a 46-year-old woman with recent-onset rheumatologic illness who developed pulmonary symptoms as the presenting feature of biphenotypic acute leukaemia. Chest radiology demonstrated bilateral infiltrates, and lung biopsy revealed nonspecific interstitial pneumonia. Corticosteroid therapy resulted in resolution of both her pulmonary and rheumatologic symptoms, and her pulmonary symptoms did not recur following treatment of her leukemia. The case highlights the importance of searching for an underlying etiology when confronted with nonspecific interstitial pneumonia.