Person: Neuberg, Donna
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Neuberg
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Donna
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Neuberg, Donna
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Publication Repression of BIM mediates survival signaling by MYC and AKT in high-risk T-cell acute lymphoblastic leukemia(2014) Reynolds, Christine; Roderick, Justine E.; LaBelle, James L.; Bird, Gregory; Mathieu, Ronald; Bodaar, Kimberly; Colon, Diana; Pyati, Ujwal; Stevenson, Kristen E.; Qi, Jun; Harris, Marian; Silverman, Lewis; Sallan, Stephen; Bradner, James E; Neuberg, Donna; Look, A.; Walensky, Loren; Kelliher, Michelle A.; Gutierrez, AlejandroTreatment resistance in T-cell acute lymphoblastic leukemia (T-ALL) is associated with PTEN deletions and resultant PI3K-AKT pathway activation, as well as MYC overexpression, and these pathways repress mitochondrial apoptosis in established T-lymphoblasts through poorly defined mechanisms. Normal T-cell progenitors are hypersensitive to mitochondrial apoptosis, a phenotype that is dependent on expression of proapoptotic BIM. In a conditional zebrafish model, MYC downregulation induced BIM expression in T-lymphoblasts, an effect that was blunted by expression of constitutively active AKT. In human T-ALL cell lines and treatment- resistant patient samples, treatment with MYC or PI3K-AKT pathway inhibitors each induced BIM upregulation and apoptosis, indicating that BIM is repressed downstream of MYC and PI3K-AKT in high-risk T-ALL. Restoring BIM function in human T-ALL cells using a stapled peptide mimetic of the BIM BH3 domain had therapeutic activity, indicating that BIM repression is required for T-ALL viability. In the zebrafish model, where MYC downregulation induces T- ALL regression via mitochondrial apoptosis, T-ALL persisted despite MYC downregulation in 10% of bim wild-type zebrafish, 18% of bim heterozygotes, and in 33% of bim homozygous mutants (P = 0.017). We conclude that downregulation of BIM represents a key survival signal downstream of oncogenic MYC and PI3K-AKT signaling in treatment-resistant T-ALL.Publication DHODH modulates transcriptional elongation in the neural crest and melanoma(Nature Publishing Group, 2011) White, Richard Mark; Cech, Jennifer; Ratanasirintrawoot, Sutheera; Lin, Charles; Rahl, Peter B.; Burke, Christopher J.; Langdon, Erin; Tomlinson, Matthew L.; Mosher, Jack; Kaufman, Charles; Chen, Frank; Long, Hannah K.; Kramer, Martin; Datta, Sumon; Neuberg, Donna; Granter, Scott; Young, Richard; Morrison, Sean; Wheeler, Grant N.; Zon, LeonardPublication The Impact of Age and Sex in DLBCL: Systems Biology Analyses Identify Distinct Molecular Changes and Signaling Networks(Libertas Academica, 2015) Beheshti, Afshin; Neuberg, Donna; McDonald, J. Tyson; Vanderburg, Charles; Evens, Andrew M.Potential molecular alterations based on age and sex are not well defined in diffuse large B-cell lymphoma (DLBCL). We examined global transcriptome DLBCL data from The Cancer Genome Atlas (TCGA) via a systems biology approach to determine the molecular differences associated with age and sex. Collectively, sex and age revealed striking transcriptional differences with older age associated with decreased metabolism and telomere functions and female sex was associated with decreased interferon signaling, transcription, cell cycle, and PD-1 signaling. We discovered that the key genes for most groups strongly regulated immune function activity. Furthermore, older females were predicted to have less DLBCL progression versus older males and young females. Finally, analyses in systems biology revealed that JUN and CYCS signaling were the most critical factors associated with tumor progression in older and male patients. We identified important molecular perturbations in DLBCL that were strongly associated with age and sex and were predicted to strongly influence tumor progression.Publication Triplication of a 21q22 region contributes to B cell transformation through HMGN1 overexpression and loss of histone H3 lysine 27 trimethylation(2014) Lane, Andrew; Chapuy, Bjoern; Lin, Charles Y.; Tivey, Trevor; Li, Hubo; Townsend, Elizabeth C.; van Bodegom, Diederik; Day, Tovah; Wu, Shuo-Chieh; Liu, Huiyun; Yoda, Akinori; Alexe, Gabriela; Schinzel, Anna; Sullivan, Timothy J.; Malinge, Sébastien; Taylor, Jordan E.; Stegmaier, Kimberly; Jaffe, Jacob D.; Bustin, Michael; te Kronnie, Geertruy; Izraeli, Shai; Harris, Marian; Stevenson, Kristen E.; Neuberg, Donna; Silverman, Lewis; Sallan, Stephen; Bradner, James E; Hahn, William; Crispino, John D.; Pellman, David; Weinstock, DavidDown syndrome confers a 20-fold increased risk of B cell acute lymphoblastic leukemia (B-ALL)1 and polysomy 21 is the most frequent somatic aneuploidy amongst all B-ALLs2. Yet, the mechanistic links between chr.21 triplication and B-ALL remain undefined. Here we show that germline triplication of only 31 genes orthologous to human chr.21q22 confers murine progenitor B cell self-renewal in vitro, maturation defects in vivo, and B-ALL with either BCR-ABL or CRLF2 with activated JAK2. Chr.21q22 triplication suppresses H3K27me3 in progenitor B cells and B-ALLs, and “bivalent” genes with both H3K27me3 and H3K4me3 at their promoters in wild-type progenitor B cells are preferentially overexpressed in triplicated cells. Strikingly, human B-ALLs with polysomy 21 are distinguished by their overexpression of genes marked with H3K27me3 in multiple cell types. Finally, overexpression of HMGN1, a nucleosome remodeling protein encoded on chr.21q223–5, suppresses H3K27me3 and promotes both B cell proliferation in vitro and B-ALL in vivo.Publication T-Lymphoblastic Lymphoma Cells Express High Levels of BCL2, S1P1, and ICAM1, Leading to a Blockade of Tumor Cell Intravasation(Elsevier BV, 2010) Feng, Hui; Stachura, David L.; White, Richard; Gutierrez, Alejandro; Zhang, Lu; Sanda, Takaomi; Jette, Cicely A.; Testa, Joseph R.; Neuberg, Donna; Langenau, David; Kutok, Jeffery Lorne; Zon, Leonard; Traver, David; Fleming, Mark; Kanki, John P.; Look, A.The molecular events underlying the progression of T-lymphoblastic lymphoma (T-LBL) to acute T-lymphoblastic leukemia (T-ALL) remain elusive. In our zebrafish model, concomitant overexpression of bcl-2 with Myc accelerated T-LBL onset while inhibiting progression to T-ALL. The T-LBL cells failed to invade the vasculature and showed evidence of increased homotypic cell-cell adhesion and autophagy. Further analysis using clinical biopsy specimens revealed autophagy and increased levels of BCL2, S1P1, and ICAM1 in human T-LBL compared with T-ALL. Inhibition of S1P1 signaling in T-LBL cells led to decreased homotypic adhesion in vitro and increased tumor cell intravasation in vivo. Thus, blockade of intravasation and hematologic dissemination in T-LBL is due to elevated S1P1 signaling, increased expression of ICAM1, and augmented homotypic cell-cell adhesion.Publication Mitochondrial Variations in Non-Small Cell Lung Cancer (NSCLC) Survival(Libertas Academica, 2015) Wang, Zhaoxi; Choi, Sojung; Lee, Jinseon; Huang, Yen-Tsung; Chen, Feng; Zhao, Yang; Lin, Xihong; Neuberg, Donna; Kim, Jhingook; Christiani, David CMutations in the mtDNA genome have long been suspected to play an important role in cancer. Although most cancer cells harbor mtDNA mutations, the question of whether such mutations are associated with clinical prognosis of lung cancer remains unclear. We resequenced the entire mitochondrial genomes of tumor tissue from a population of 250 Korean patients with non-small cell lung cancer (NSCLC). Our analysis revealed that the haplogroup (D/D4) was associated with worse overall survival (OS) of early-stage NSCLC [adjusted hazard ratio (AHR), 1.95; 95% CI, 1.14–3.33; Ptrend = 0.03]. By comparing the mtDNA variations between NSCLC tissues and matched blood samples, we found that haplogroups M/N and/or D/D4 were hotspots for somatic mutations, suggesting a more complicated mechanism of mtDNA somatic mutations other than the commonly accepted mechanism of sequential accumulation of mtDNA mutations.Publication Amino acid–insensitive mTORC1 regulation enables nutritional stress resilience in hematopoietic stem cells(American Society for Clinical Investigation, 2017) Kalaitzidis, Demetrios; Lee, Dongjun; Efeyan, Alejo; Kfoury, Youmna; Nayyar, Naema; Sykes, David; Mercier, Francois; Papazian, Ani; Baryawno, Ninib; Victora, Gabriel D.; Neuberg, Donna; Sabatini, David; Scadden, DavidThe mTOR pathway is a critical determinant of cell persistence and growth wherein mTOR complex 1 (mTORC1) mediates a balance between growth factor stimuli and nutrient availability. Amino acids or glucose facilitates mTORC1 activation by inducing RagA GTPase recruitment of mTORC1 to the lysosomal outer surface, enabling activation of mTOR by the Ras homolog Rheb. Thereby, RagA alters mTORC1-driven growth in times of nutrient abundance or scarcity. Here, we have evaluated differential nutrient-sensing dependence through RagA and mTORC1 in hematopoietic progenitors, which dynamically drive mature cell production, and hematopoietic stem cells (HSC), which provide a quiescent cellular reserve.In nutrient-abundant conditions, RagA-deficient HSC were functionally unimpaired and upregulated mTORC1 via nutrientinsensitive mechanisms. RagA was also dispensable for HSC function under nutritional stress conditions. Similarly, hyperactivation of RagA did not affect HSC function. In contrast, RagA deficiency markedly altered progenitor population function and mature cell output. Therefore, RagA is a molecular mechanism that distinguishes the functional attributes of reactive progenitors from a reserve stem cell pool. The indifference of HSC to nutrient sensing through RagA contributes to their molecular resilience to nutritional stress, a characteristic that is relevant to organismal viability in evolution and in modern HSC transplantation approaches.Publication Phase I study of the aurora A kinase inhibitor alisertib with induction chemotherapy in patients with acute myeloid leukemia(Ferrata Storti Foundation, 2017) Fathi, Amir; Wander, Seth; Blonquist, Traci M.; Brunner, Andrew; Amrein, Philip; Supko, Jeffrey; Hermance, Nicole M.; Manning, Amity L.; Sadrzadeh, Hossein; Ballen, Karen K.; Attar, Eyal C.; Graubert, Timothy; Hobbs, Gabriela; Joseph, Christelle; Perry, Ashley M.; Burke, Meghan; Silver, Regina; Foster, Julia; Bergeron, Meghan; Ramos, Aura Y.; Som, Tina T.; Fishman, Kaitlyn M.; McGregor, Kristin L.; Connolly, Christine; Neuberg, Donna; Chen, Yi-BinAberrant expression of aurora kinase A is implicated in the genesis of various neoplasms, including acute myeloid leukemia. Alisertib, an aurora A kinase inhibitor, has demonstrated efficacy as monotherapy in trials of myeloid malignancy, and this efficacy appears enhanced in combination with conventional chemotherapies. In this phase I, dose-escalation study, newly diagnosed patients received conventional induction with cytarabine and idarubicin, after which alisertib was administered for 7 days. Dose escalation occurred via cohorts. Patients could then receive up to four cycles of consolidation, incorporating alisertib, and thereafter alisertib maintenance for up to 12 months. Twenty-two patients were enrolled. One dose limiting toxicity occurred at dose level 2 (prolonged thrombocytopenia), and the recommended phase 2 dose was established at 30mg twice daily. Common therapy-related toxicities included cytopenias and mucositis. Only three (14%) patients had persistent disease at mid-cycle, requiring “5+2” reinduction. The composite remission rate (complete remission and complete remission with incomplete neutrophil recovery) was 86% (nineteen of twenty-two patients; 90% CI 68–96%). Among those over age 65 and those with high-risk disease (secondary acute leukemia or cytogenetically high-risk disease), the composite remission rate was 88% and 100%, respectively. The median follow up was 13.5 months. Of those treated at the recommended phase 2 dose, the 12-month overall survival and progression-free survival were 62% (90% CI 33–81%) and 42% (90% CI 17–65%), respectively. Alisertib is well tolerated when combined with induction chemotherapy in acute myeloid leukemia, with a promising suggestion of efficacy. (clinicaltrials.gov Identifier:01779843).Publication Identification of a myeloid committed progenitor as the cancer-initiating cell in acute promyelocytic leukemia(American Society of Hematology, 2009) Guibal, F. C.; Alberich-Jorda, M.; Hirai, H.; Ebralidze, Alexander; Levantini, Elena; Di Ruscio, A.; Zhang, Pu; Santana-Lemos, B. A.; Neuberg, Donna; Wagers, Amy; Rego, E. M.; Tenen, DanielAcute promyelocytic leukemia (APL) is characterized by a block in differentiation and accumulation of promyelocytes in the bone marrow and blood. The majority of APL patients harbor the t(15:17) translocation leading to expression of the fusion protein promyelocytic-retinoic acid receptor . Treatment with retinoic acid leads to degradation of promyelocyticretinoic acid receptor protein and disappearance of leukemic cells; however, 30% of APL patients relapse after treatment. One potential mechanism for relapse is the persistence of cancer “stem” cells in hematopoietic organs after treatment. Using a novel sorting strategy we developed to isolate murine myeloid cells at distinct stages of differentiation, we identified a population of committed myeloid cells (CD34, c-kit, FcRIII/II, Gr1int) that accumulates in the spleen and bone marrow in a murine model of APL. We observed that these cells are capable of efficiently generating leukemia in recipient mice, demonstrating that this population represents the APL cancer–initiating cell. These cells down-regulate the transcription factor CCAAT/enhancer binding protein (C/EBP) possibly through a methylationdependent mechanism, indicating that C/EBP deregulation contributes to transformation of APL cancer–initiating cells. Our findings provide further understanding of the biology of APL by demonstrating that a committed transformed progenitor can initiate and propagate the disease.Publication Detecting T-cell Reactivity to Whole Cell Vaccines(Landes Bioscience, 2012) Brusic, Ana; Hainz, Ursula; Wadleigh, Martha; Neuberg, Donna; Su, Mei; Canning, Christine M.; DeAngelo, Daniel; Stone, Richard; Lee, Jeng-Shin; Mulligan, Richard; Ritz, Jerome; Dranoff, Glenn; Sasada, Tetsuro; Wu, CatherineBCR-ABL\(^+\) K562 cells hold clinical promise as a component of cancer vaccines, either as bystander cells genetically modified to express immunostimulatory molecules, or as a source of leukemia antigens. To develop a method for detecting T-cell reactivity against K562 cell-derived antigens in patients, we exploited the dendritic cell (DC)-mediated cross-presentation of proteins generated from apoptotic cells. We used UVB irradiation to consistently induce apoptosis of K562 cells, which were then fed to autologous DCs. These DCs were used to both stimulate and detect antigen-specific CD8+ T-cell reactivity. As proof-of-concept, we used cross-presented apoptotic influenza matrix protein-expressing K562 cells to elicit reactivity from matrix protein-reactive T cells. Likewise, we used this assay to detect increased anti-CML antigen T-cell reactivity in CML patients that attained long-lasting clinical remissions following immunotherapy (donor lymphocyte infusion), as well as in 2 of 3 CML patients vaccinated with lethally irradiated K562 cells that were modified to secrete high levels of granulocyte macrophage colony-stimulating factor (GM-CSF). This methodology can be readily adapted to examine the effects of other whole tumor cell-based vaccines, a scenario in which the precise tumor antigens that stimulate immune responses are unknown.