Characterizing normal hematopoiesis and defining genetic alterations associated with hematologic malignancies

Research Team:  Chiu, Eklund, Guitart, Kansas, Krett, Licht, Longnecker, Miller, Papoutsakis, Peterson, Platanias, Rosen, Singhal, Stein, Yaseen, Wang, Winandy

The members of the Hematologic Malignancies Program have made significant contributions to understanding the pathogenesis of malignant hematologic disease, many of which are being extended into testing of novel therapeutic compounds to target these abnormalities.

The Program has an active group involved in identifying molecular defects in myeloid leukemias. The laboratory of Dr. Leonidas Platanias has a major focus on disruption in signaling pathways in malignant myeloid cells. Their studies have lead to important insights into abnormalities in signal transduction pathways activated by interferon and retinoic acid receptors. These abnormalities involve PKC, p38 MAPK and mTOR, which are all rationale therapeutic targets. The laboratories of Drs. Nabeel Yaseen and Dr. Elizabeth Eklund have been identifying target genes for Hox proteins and leukemia associated Hox-fusion proteins. These studies are designed to better understand Hox code function in normal and malignant myelopoiesis. Identification of Hox target genes may suggest rational targets for therapeutic interventions in myeloid leukemia. Drs. Platanias and Eklund have been investigating the role of protein tyrosine phosphatases in cytokine hypersensitivity in myeloproliferative disorders. These studies have lead to a translational project which is discussed further below. The laboratories of Drs. E Papoutsakis and William Miller have been using high through put screening to determine the transcriptome of differentiating hematopoietic stem cells. The goal of these studies is to determine the optimum conditions for clinical applications. The recruitment of Dr. Jonathan Licht will enhance several of these programs. Dr. Licht's laboratory focuses of molecular pathogenesis of acute leukemia. Among his contributions include seminal observations regarding the activating mutations in Jak2-protein tyrosine kinase and SHP2-protein tyrosine phosphatase in myeloproliferative disorders and myeloid leukemia.

The Hematological Malignancies Program also has laboratory investigators pursuing the identification of molecular abnormalities involved in lymphoid malignancies. Drs. Steven Rosen and Nancy Krett have a long-standing program in the molecular biology of glucocorticoid resistance in multiple myeloma. Their studies of the molecular mechanisms of resistance have lead to identification of novel therapeutic targets, as discussed below. As at the time of the previous program review, Drs. Rosen and Krett continue to be leaders in translating laboratory observations to the clinic. In collaboration with Dr. Singhal, they are extending their analysis of critical signaling pathways in multiple myeloma. Dr. Susan Winandy has been studying dysregulation of Ikaros expression in T-cell lymphoma and leukemia. Her basic sciences studies provide key insights into cell cycle regulation in T-cell leukemia and lymphoma. Dr. Richard Longnecker has a longstanding program investigating the biology of EBV infection And he is a nationally recognized leader in the molecular biology of EBV related cellular transformation. Since the last program review, Dr. Longnecker has formed a collaboration with Dr. Leo Gordon to investigate the impact of latent EBV infection on disease progression or initiation in lymphoma in immuno-compromised patients and within the Eastern Oncology Group, Dr. Winter has led correlative studies in the diffuse large B-cell lymphomas investigating important prognostic indicators such as bcl-6, bcl-2, p53 and p21 expression, identifying subsets that will require specific therapeutic strategies.

Previous Page