Leukemia and Lymphoma Research

Through discovery, innovation and collaboration, researchers at the Aflac Cancer and Blood Disorders Center of Children's Healthcare of Atlanta are investigating safer, less toxic and more effective methods of treatment for children with cancer. Program themes include:

  • Aberrant signaling nodes
  • Novel drugs and combinations

Clinical and Translational Research

  • Innovative therapy
    • Dr. Todd Cooper focuses his research efforts on developing novel drugs for clinical study in relapsed leukemia patients. Currently, Dr. Cooper is the lead investigator of two Phase I clinical trials for relapsed leukemia patients that are being conducted in selected institutions throughout the country. The first trial is an Aflac Cancer Center initiated study of a  specific drug that appears to push hidden leukemia cells into circulation—allowing them to be destroyed by chemotherapy. The second is a clinical trial of a drug that could be useful in treating children with a specific mutation in their leukemia that leads to devastating outcomes. Learn more
  • Nano-scale Proteomics
    • The NanoPro 1000 system (cell biosciences) enables a rapid and quantitative analysis of specific proteins from as few as 25 cells per sample. Drs. Kevin Bunting and Himalee Sabnis, along with a senior research technician Heath Bradley, use the automated, capillary based immunoassay platform to obtain precise and quantitative data of the phosphorylation states of proteins separated by isoelectric focusing. The instrument is capable of analyzing dozens of different proteins within a single sample or it can analyze a single protein in up to 96 samples per run.  The group is developing assays for profiling of signaling pathways in valuable patient samples.
  • mTOR targeted therapies
    • Drs. Frank Keller (ALL) and Kevin Bunting and Himalee Sabnis (AML) are focused on effectively inhibiting the mTOR pathway using innovative approaches in combination with rapamycin which alone is not very effective at suppressing protein synthesis downstream of a highly activated PI3K/AKT/mTOR pathway.

Clinical and Translational Researchers

     
 
MDM2Research

    While the activation of p53 is well known, Drs. Zhou and Gu have discovered that MDM2 has two major effects. They found that MDM2 also associates directly with XIAP to stabilize the protein. Therefore, blocking the interaction of MDM2 with XIAP could kill cancer cells liberation of p53, but also through induction of caspase mediated apoptosis.

  
     

Basic Research

  • Targeting MDM2 Signaling in Cancer Treatment
    • Drs. Muxiang Zhou and Lubing Gu are searching for small-molecule compounds that insulate the connections between MDM2 and XIAP. This insulating effect disrupts the signals from MDM2 to boost the production of the cancer-resistant XIAP—allowing cancer cells to become more sensitive to chemotherapy. Learn more
  • Targeting STAT5/mTOR Signaling
    • Dr. Kevin Bunting specializes in studying a molecule called STAT5, which shows great promise as a treatment that would greatly reduce unwanted side effects, like those associated with radiation. STAT5 could also lead to a revolutionary treatment of childhood cancer and other diseases. Learn more
  • STAT5
    • Dr. Bunting’s research is focused on understanding the biology of the latent transcription factor STAT5, in particular, its roles in normal hematopoietic stem cell function and its aberrant activation associated with a variety of hematologic malignancies. 
      • Activation of STAT5 by phosphorylation is required at tightly regulated levels for normal hematopoiesis, but its persistent activation is prevalent in adult and pediatric leukemias. 
      • A major focus of the Bunting lab is to identify key STAT5 downstream target genes associated with both normal and leukemic hematopoietic cell function and to utilize this knowledge to develop novel approaches to manipulate STAT5 activity in a therapeutic setting. 
        • In leukemia therapy, the goal is to disengage leukemic cell survival and to facilitate leukemia cell sensitivity in combination with other targeted agents. 
        • In hematopoietic stem cell transplantation, the goal is to develop innovative forms of conditioning based on STAT5 signaling inhibition. 
    • Dr. Bunting also studies the Grb2-associated binding (Gab) family of adapter proteins and their role in PI3K-AKT-mTOR activation in hematopoietic and immune cell biology. The Gab family of scaffolding adapter proteins are synergistic with STAT5 in controlling hematopoietic stem cell self-renewal and leukemogenesis and thus represent an attractive cooperative signaling node in which to focus on therapeutics targeting both STAT5 and AKT mediated signals.

Basic Researchers

Recent Publications

  • Dreyer Z, Dinndorf PA, Camitta BM, Sather H, La MK, Devidas M, Hilden JM, Heerema NA, Sanders JE, McGlennen R, Willman CL, Carroll AJ, Behm FG, Smith FO, Woods WG, Godder K, and Reaman GH.  Analysis of the Role of Hematopoietic Stem Cell Transplantation in Infants with Acute Lymphoblastic Leukemia in First Remission and MLL Gene Rearrangements: A report from the Children's Oncology Group.  J Clin Oncol, 2010.  [Epub ahead of print.] doi: 10.1200/JCO.
  • Friedbichler K, Kerenyi MA, Kovacic B, Li G, Hoelbl A, Yahiaoui S, Sexl V, Mullner EW, Beug H, Gouilleux F, Bunting KD, Moriggl R.  Stat5a serine 725 and 779 phosphorylation is a prerequisite for hematopoietic transformation.  Blood 2010;116:1548-1558.
  • Hazen RA, Eder M, Drotar D, Zyzanski S, Reynolds AE, Reynolds CP, Kodish E, Noll RB; Collaborators: Angiolillo A, Feusner J, Khayat A, Lew G, Reilly A, Ruccione K. A feasibility trial of a video intervention to improve informed consent for parents of children with leukemia.  Pediatr Blood Cancer 2010; 55:10-1.
  • Johnston DL, Alonzo TA, Gerbing RB, Lange BJ, and Woods WG.  The Presence of Central Nervous System Disease at Diagnosis in Pediatric Acute Myeloid Leukemia Does Not Affect Survival: A Children’s Oncology Group Study.  Pediatr Blood Cancer 2010;55:414-420.
  • Ko JS, Rayman P, Ireland J, Swaidani S, Biswas S, Biswas K, Rini B, Li G, Bunting KD, Rini B, Finke JH, Cohen PC.  Direct and differential suppression of myeloid-derived suppressor cell subsets by sunitinib is compartmentally constrained.  Cancer Research, 2010;70:3526-36.
  • Li G, Miskimen KL, Wang Z, Xie XY, Brenzovich J, Ryan JJ, Tse W, Moriggl R, Bunting KD.  STAT5 requires the N-domain for suppression of miR15/16, induction of bcl-2, and survival signaling in myeloproliferative disease.  Blood 2010;115,1416-1424.
  • Li G, Miskimen KL, Wang Z, Xie XY, Tse W, Gouilleux F, Moriggl R, Bunting KD. “Effective targeting of STAT5-mediated survival in myeloproliferative neoplasms using ABT-737 combined with rapamycin”.  Leukemia 2010;24:1397-1405.
  • Li G, Wang Z, Miskimen KL, Zhang Y, Tse W and Bunting KD.  “Gab2 promotes hematopoietic stem cell maintenance and self-renewal synergistically with STAT5”.  PLos ONE 2010;5:e9152
  • Ling X, Calinski D, Chana-Khan AA, Zhou M, Li F. Cancer cell sensitivity to bortezamib is associated with survivin expression and p53 status but not cancer cell types. J Exp Clin Cancer Res 2010;29:8-18. 
  • Pollard JA, Alonzo T, Gerbing RB, Ho P, Zeng R, Ravindranath Y, Dahl G, Lacayo N, Becton D, Chang MN, Weinstein HJ, Hirsch B, Raimondi SC, Heerema NA, Woods WG, Lange B, Hurwitz C, Arceci RJ, Radich JP, Bernstein ID, Heinrich M, and Meshinchi S.  Prevalence and prognostic significance of KIT mutations in pediatric core binding factor AML patients enrolled on serial pediatric cooperative trials for de novo AML.  Blood, 2010;115:2372-2379.
  • Robertson VL, Anderson CS, Keller FG, Halkar R, Goodman M, Marcus RB, Esiashvili N.  Role of FDG-PET in the Definition of Involved-Field Radiation Therapy and Management for Pediatric Hodgkin's Lymphoma.  Int J Radiat Oncol Biol Phys. 2010 Jun 18. [Epub ahead of print] PMID: 20646867.
  • Schultz KAP, Chen L, Chen Z, Kawashima T, Oeffinger KC, Woods WG, Nicholson HS, Neglia JP.  Health-Related Quality of Life and Chronic Health Conditions in Survivors of Childhood Acute Myeloid Leukemia (AML): A Report from the Children’s Oncology Group.  Pediatr Blood Cancer 2010;55:157–164.
  • Wayne AS, Kreitman RJ, Findley HW, Lew G, Delbrook C, Steinberg SM, Stetler-Stevenson M, FitzGerald DJ, Pastan I.  Anti-CD22 Immunotoxin RFB4(dsFv)-PE38 (BL22) for CD22-Positive Hematologic Malignancies of Childhood: Preclinical Studies and Phase I Clinical Trial.  Clin Cancer Res 2010 March; 16(6):1894-1903. 
  • Xu D, Wang S, Yu WM, Chan G, Araki T, Bunting KD, Neel BG, Qu CK:  A germline gain-of-function mutation of Ptpn11 (Shp-2) phosphatase induces myeloproliferative disease by aberrant activation of hematopoietic stem cells.  Blood 2010; 116: 3611-3621.
  • Yang L, Gu L, Li Z and Zhou M. Translation of TRAF1 is regulated by IRES-dependent mechanism and stimulated by vincristine. Nucleic Acids Res. 2010;38:4503-4513. 
  • Zhang X, Gu L, Li J, Shah N, He J, Yang L, Hu Q, Zhou M. Degradation of MDM2 by the interaction between berberine and DAXX leads to potent apoptosis in MDM2-overexpressing cancer cells. Cancer Res. 2010;70:9895-9904.

Research Collaborations

The Aflac Cancer Center conducts leading-edge research in conjunction with the following local, regional and national organizations: