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Publications (3)30.2 Total impact

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    ABSTRACT: The incidence of mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in de novo acute myeloid leukemia (AML) is approximately 20%. These mutations result in distinct metabolic characteristics including dependency of cancer cells on glutamine as the main source for α-ketoglutarate, which is consumed by leukemia cells to produced a cancer-derived metabolite, 2-hydroxyglutarate. We sought to therapeutically exploit this glutamine addiction in mutant IDH primary AML cells from patients by measuring cell growth after exposure to a small molecule glutaminase inhibitor, BPTES. We found that BPTES only suppressed the growth of AML cells expressing mutant IDH compared with those expressing wild-type IDH. This study lays the ground for strategies to metabolically target a specific subtype of AML with IDH mutations with a unique reprogramming of intermediary metabolism which culminates in glutamine dependency of cancer cells for survival.
    Experimental hematology 12/2013; · 3.11 Impact Factor
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    ABSTRACT: Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a non-invasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrates that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared to DNA-methyltransferase inhibitor therapy. Our data suggests that serum or urine 2-HG may serve as non-invasive biomarkers of disease activity for IDH-mutant AML.
    Blood 10/2012; · 9.06 Impact Factor
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    ABSTRACT: Background: MDS is comprised of a heterogeneous group of clonal myeloid disorders. Chronic immune stimulation has been reported as a trigger for the development of a subset of MDS, with increased autoreactive cytotoxic T cells present in the bone marrow. Autoimmunity has been associated with MDS and other marrow failures. DNMTIs, 5-azacytidine and decitabine, are approved for the treatment of MDS. In addition to epigenetic impacts, these agents may have immunomodulatory effects, including augmentation of MAGE-related anti-tumor response. These reports and clinical observations led us to hypothesize that MDS patients with a history of autoimmunity may be more responsive to DNMTIs. Methods: To identify patients with MDS, a retrospective database review (2007-2011) was performed at Johns Hopkins Hospital (JHH) and Massachusetts General Hospital (MGH). The MGH data also included those with AML whose disease had progressed from MDS. Past medical history of autoimmune disorders, diagnosis, blood counts, flow cytometry and cytogenetics were reviewed. Patients with aplastic anemia, paroxysmal nocturnal hemoglobinuria or non-malignant etiologies of cytopenia were excluded. Patients with MDS were further studied if they were treated with DNMTI. Results: Of 137 patients with MDS or MDS/AML, 23 had a documented history of autoimmunity in the medical record. Of these, 15 (65.2%) experienced a response to therapy as defined by the International Working Group. Of 114 patients without a documented history of autoimmunity, 34 (29.8%) achieved a response during therapy, a significantly lower percentage as compared to those with autoimmune conditions (p-value 0.002, t-test). The majority of responding patients with a history of autoimmunity displayed a normal karyotype (9 of 15 patients). Conclusions: A history or co-presence of an autoimmune disorder may predict a high likelihood of achieving a clinical response to DNMTIs. Correlative studies in this unique population of patients with MDS and MDS/AML and prospective clinical studies are needed to improve our understanding of the possible mechanism of action of DNMTIs in these patients.
    Journal of Clinical Oncology 05/2012; J Clin Oncol 30, 2012 (suppl; abstr 6629)(30). · 18.04 Impact Factor