Person:
Harris, Marian

Profile Picture

Email Address

AA Acceptance Date

Birth Date

Research Projects

Organizational Units

Job Title

Last Name

Harris

First Name

Marian

Name

Harris, Marian
Author's Publications: search.filters.isAuthorOfPublication.d61feb88-0297-43f2-8125-e77da340aa82

Search Results

Now showing 1 - 3 of 3
  • Thumbnail Image
    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, Alejandro
    Treatment 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.
  • No Thumbnail Available
    Publication
    Recurrent EML4–NTRK3 fusions in infantile fibrosarcoma and congenital mesoblastic nephroma suggest a revised testing strategy
    (Springer Science and Business Media LLC, 2017-11-03) Church, Alanna; Calicchio, Monica; Nardi, Valentina; Skálová, Alena; Pinto, Andre; Dillon, Deborah; Gomez-Fernandez, Carmen; Manoj, Namitha; Haimes, Josh; Stahl, Joshua; Dela Cruz, Filemon; Tannenbaum-Dvir, Sarah; Glade-Bender, Julia; Kung, Andrew; DuBois, Steven; Kozakewich, Harry; Janeway, Katherine; Perez-Atayde, Antonio; Harris, Marian
  • Thumbnail Image
    Publication
    Characterization of a novel fusion gene EML4-NTRK3 in a case of recurrent congenital fibrosarcoma
    (Cold Spring Harbor Laboratory Press, 2015) Tannenbaum-Dvir, Sarah; Glade Bender, Julia L.; Church, Alanna; Janeway, Katherine; Harris, Marian; Mansukhani, Mahesh M.; Nagy, Peter L.; Andrews, Stuart J.; Murty, Vundavalli V.; Kadenhe-Chiweshe, Angela; Connolly, Eileen P.; Kung, Andrew L.; Dela Cruz, Filemon S.
    Abstract We describe the clinical course of a recurrent case of congenital fibrosarcoma diagnosed in a 9-mo-old boy with a history of hemimelia. Following complete surgical resection of the primary tumor, the patient subsequently presented with bulky bilateral pulmonary metastases 6 mo following surgery. Molecular characterization of the tumor revealed the absence of the prototypical ETV6-NTRK3 translocation. However, tumor characterization incorporating cytogenetic, array comparative genomic hybridization, and RNA sequencing analyses, revealed a somatic t(2;15)(2p21;15q25) translocation resulting in the novel fusion of EML4 with NTRK3. Cloning and expression of EML4-NTRK3 in murine fibroblast NIH 3T3 cells revealed a potent tumorigenic phenotype as assessed in vitro and in vivo. These results demonstrate that multiple fusion partners targeting NTRK3 can contribute to the development of congenital fibrosarcoma.