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Group Moriggl

Leukemogenesis studies with persistently activated forms of Stat5

Network Contribution

Leukemia derives from clonal variants that carry multiple genetic lesions and mutations can become dominant and transform to full disease. Such clones have increased repopulation capacity in competitive transplants, e.g. due to decreased cytokine dependence, often observed upon mutation of a tyrosine kinase. High pYStat5 is regarded as a general promoter of hematopoietic cancers, although normal Stat5 function safeguards hematopoiesis. The Jak2-Stat5 pathway drives several core cancer pathways but can also promote differentiation or senescence.
In SFB-P07RM we are studying signaling through the Jak2 kinase and Stat5 transcription factors in tumorigenesis. Exploiting new mouse models we are investigating hematopoietic cancer development in mice harboring Jak2 and Stat5 gain-of-function mutants combined with loss of tumor suppressor protein function. Both Jak2 and Stat5 activation (pYStat5) are hematopoietic cancer drivers. Together with SFB-P08MM we have developed three new gain-of-function Stat5a mouse models to provide reliable systems to study cancer. We are performing the research in close collaboration with SFB-P12RK to test tumor suppressor proteins that synergize with oncogenic Stat5 (cS5) and to profile them genetically. High or low cS5 activity is surprisingly well tolerated in hematopoietic cells and transgenic cS5 mice displayed no leukemia early in life.
The following two main hypotheses are central to the project part:
(1) Jak2-Stat5 signaling is only oncogenic if accompanied by loss of tumor suppressor proteins.
(2) Stat5 activity gradually increases in the clonal population upon disease progression.
To test both hypotheses we have developed three inducible transgenic lines with cS5 expression in hematopoietic lineages. First, we evaluated inducible cS5 expression using a BAC transgenic approach (called icS5 and described in the report). We found that cS5 induction did not cause neoplasia but we observed cooperativity with haploinsufficient PTEN loss. Next, we developed two transgenic mouse lines (in the following abbreviated as vcS5 mice) with high (vcS5high) or low cS5 (vcS5low) levels of activation. The expression of cS5 is restricted to hematopoietic cells and developmentally starts in the hematopoietic stem cell (HSC) stage. The first hypothesis will be tested by combining and creating compound mouse models with haploinsufficient loss of important tumor suppressor proteins (IKZF1, SOCS2, CUX1 or PTEN) that may be expected to cooperate with cS5. The second hypothesis will be tested with murine models of cS5 in combination with the heterozygous oncogenic Jak2V617F/+ knockin mice. In summary, compound mouse models should develop cancers with different disease aggravation to myeloproliferative neoplasm (MPN), leukemia or lymphoma.

Goals and Key Hypotheses:
Specific hypotheses
(1) High or low pYStat5 levels in hematopoietic lineages affect hematopoiesis differently.
(2) pYStat5 cooperates with loss of tumor suppressors to cause hematopoietic cancers.
(3) pYStat5 can activate distinct signaling pathways to support cancers.
(4) Murine models expressing pYStat5 are suitable to test novel therapies based on pharmacological interference with Jak-Stat activation.
Specific Goals of the proposal part:
(1) Mimic hematopoietic cancer development through low or high gene dosage of pYStat5.
(2) Determine which clonal expansions of hematopoietic cells cause disease.
(3) Perform RNA-Seq expression analysis to identify cancer driver pathways.
4) Explore therapeutic interference strategies and specific use of Jak-Stat inhibitors.

Antwort auf/zuklappen Report on funding period 1 (03/2006-03/2010)

Antwort auf/zuklappen Report on funding period 2



Ludwig Boltzmann Institute for Cancer Research (LBI-CR)
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