• Genetic-or compound CB-839-induced GAC inhibition reduces OXPHOS and has antileukemic activity in AML.• GAC inhibition synergizes with BCL-2 inhibition by compound ABT-199.Cancer cells require glutamine to adapt to increased biosynthetic activity. The limiting step in intracellular glutamine catabolism involves its conversion to glutamate by glutaminase (GA). Different GA isoforms are encoded by the genes GLS1 and GLS2 in humans. Herein, we show that glutamine levels control mitochondrial oxidative phosphorylation (OXPHOS) in acute myeloid leukemia (AML) cells. Glutaminase C (GAC) is the GA isoform that is most abundantly expressed in AML. Both knockdown of GLS1 expression and pharmacologic GLS1 inhibition by the drug CB-839 can reduce OXPHOS, leading to leukemic cell proliferation arrest and apoptosis without causing cytotoxic activity against normal human CD34 1 progenitors. Strikingly, GLS1 knockdown dramatically inhibited AML development in NSG mice. The antileukemic activity of CB-839 was abrogated by both the expression of a hyperactive GAC K320A allele and the addition of the tricarboxyclic acid cycle product a-ketoglutarate, indicating the critical function of GLS1 in AML cell survival. Finally, glutaminolysis inhibition activated mitochondrial apoptosis and synergistically sensitized leukemic cells to priming with the BCL-2 inhibitor ABT-199. These findings show that targeting glutamine addiction via GLS1 inhibition offers a potential novel therapeutic strategy for AML. (Blood. 2015;126(11):1346-1356

Kaposi Sarcoma-associated herpesvirus/ Human Herpesvirus 8 (KSHV/HHV8) associated multicentric Castleman disease (MCD) is a polyclonal B cell lymphoproliferative disorder mainly occurring in immunocompromised hosts. The diagnosis relies on lymph node biopsy demonstrating KSHV infected cells located in the mantle zone with a marked interfollicular plasma-cell infiltration. Infected cells are large cells positive for IgM,  light chain, and CD38, described initially as infected "plasmablasts". We show that IgM+λ+CD38high cells were also detectable in the peripheral blood of 14/18 (78%) patients with active KSHV-MCD and absent from 40 controls. Using immunofluorescence and flow-FISH, we demonstrate that these cells are KSHV infected and expressed both latent and lytic KSHV transcripts. These KSHV infected viroblasts (KIV) harbor a distinct phenotype compared to conventional plasmablasts. We also identified several putative mechanisms of immune escape used by KSHV, as KIV displayed an overall decrease of co-stimulatory molecules with a remarkable lack of CD40 expression and are IL-10 producing cells. The identification of this specific and easily accessible KSHV+ circulating population brings new elements in the understanding of KSHV-MCD but also raises new questions that need to be clarified.

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