Genetic Analysis of Myeloproliferative Disease

  • Cowell, John Kenneth (PI)
  • COWELL, JOHN (PI)
  • COWELL, JOHN (PI)
  • COWELL, JOHN (PI)
  • COWELL, JOHN (PI)
  • COWELL, JOHN (PI)
  • COWELL, JOHN (PI)

Project: Research project

Project Details

Description

Abstract The stem cell leukemia/lymphoma syndrome (SCLL) is unique in that it is the only cancer syndrome that results consistently from the ligand independent activation of FGFR1 tyrosine kinase. Presenting as a myeloproliferative disorder it rapidly progresses to AML and in many cases patients develop biphenotypic T- cell or B-cell lymphomas. The consensus thinking is that FGFR1 promotes a stem cell expansion which can progress and develop depending on the subsequent acquisition of oncogenic events. This disease provides a unique opportunity to investigate basic genetic events associated with maintenance of a stem cell phenotype as well as the events that allow progression to AML. We have developed mouse models for SCLL using retroviral transduction and transplantation of human and mouse stem cells which recapitulate the primary human disease. These models have facilitated a detailed analysis of the genetic events that accompany progression of SCLL allowing development of strategies to treat this disease. We recently identified a series of unexpected and unique insights into the development of the disease which are paradigm shifting. While the consensus understanding has been that the phosphoactivated kinase leads to disease development as a result of direct activation of target proteins, we have demonstrated recently that the chimeric kinases can be enzymatically cleaved to a truncated form (nFGFR1) that carries only the kinase domain and that this is located exclusively in the nucleus and is not phosphorylated. Transduction experiments show that the nFGFR1 is capable of transforming hematopoietic stem cells on its own which maintain a stem cell phenotype. These observations suggest that transformation is due to a transcription factor role of nFGFR1 leading to activation of specific genes and further, that drugs currently designed to target the phosphorylated parental kinase will not cure the disease. The systems we have developed will allow identification of the nFGFR1 targets and allow rational design of synthetic lethal approaches to eliminate the stem cells and mature leukemic cells. Our genomic study of SCLL has demonstrated a role for specific microRNAs in disease development. During this process we demonstrated that SCLL cells are immunogenic and that miR339 facilitates escape from immune tolerance and promotes escape from the immune suppression of the microenvironment. The cell systems we have developed allow mechanistic studies of the underlying causes. This study is particularly timely, since one key open question in the field is the molecular mechanisms behind how tumor cells manipulate their microenvironment so as to actively create immmuno-suppression and tolerance, and thus evade the immune system. These tumor-intrinsic pathways are still largely unknown. The miR339 system provides a striking ?on/off? system of inducible immunosuppression, that instantly converts tumor cells from immunogenic and non-lethal to immunosuppressive and lethal. This facilitates the opportunity to obtain a better understanding of the mechanism of escape from immune suppression in the context of AML.
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