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SUMMARY:Driver Mutations in Myeloproliferative Neoplasms and Secondary Mye
 loid Leukemia: From JAK2 V617F to a Mutated Chaperone - Prof Stefan Consta
 ntinescu (Head\, Signal Transduction & Molecular Hematology Unit\, Ludwig 
 Institute for Cancer Research\, Brussels\, Belgium)
DTSTART;VALUE=DATE-TIME:20180111T110000Z
DTEND;VALUE=DATE-TIME:20180111T120000Z
UID:https://talks.ox.ac.uk/talks/id/68da99b3-b420-4822-aa65-352f421086c6/
DESCRIPTION:Myeloproliferative Neoplasms (MPNs) are clonal diseases of the
  hematopoietic stem cells (HSC) that lead to excessive myeloid blood cell 
 formation. They start when a HSC acquires either the activating JAK2 V617F
  mutation\, or mutations in thrombopoietin receptor (TpoR/MPL)\, or frame-
 shift mutations in the chaperone calreticulin (CALR). After contributing t
 o the identifying JAK2 V617F and TpoR W515 mutations\, we defined the stru
 ctural bases of their pathologic (cytokine-independent) activation. This i
 nvolves a specific pseudokinase-to-kinase domain circuit for JAK2 V617F an
 d a helix to coil conformational change in the TpoR cytosolic domain for t
 he TpoR W515 mutants. More recently\, we showed that frame-shift mutants o
 f CALR acquire the ability to bind and activate TpoR in the secretory path
 way and at the cell surface\, also leading to JAK2-STAT activation in the 
 megakaryocytic lineage. We use structure-function analysis of driver mutan
 ts for identifying JAK2/TpoR and CALR mutant specific inhibitors. \n\nA fr
 action of MPN patients evolve to severe secondary acute myeloid leukemia (
 sAML)\, which has a very poor prognosis. In contrast to de novo AML\, p53 
 mutants are detected in 25% of sAML\, while another 20-% of sAML harbor am
 plification of MDM4 inhibitor of p53. We identified a cross-talk between p
 ersistently activated STAT5 and p53 mutants during progression of MPNs to 
 secondary AML. We found that all p53 mutants described in sAML\, irrespect
 ive of their own transcriptional activity\, share the ability to unleash S
 TAT5\, which appears crucial for leukemia progression. Chromatin effects o
 f unleashed STAT5 are discussed with respect of self-renewal and different
 iation during progression of MPNs to sAML.\n\nSpeakers:\nProf Stefan Const
 antinescu (Head\, Signal Transduction & Molecular Hematology Unit\, Ludwig
  Institute for Cancer Research\, Brussels\, Belgium)
LOCATION:NDM Building (Basement seminar room\, TDI)\, Headington OX3 7FZ
TZID:Europe/London
URL:https://talks.ox.ac.uk/talks/id/68da99b3-b420-4822-aa65-352f421086c6/
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DESCRIPTION:Talk:Driver Mutations in Myeloproliferative Neoplasms and Seco
 ndary Myeloid Leukemia: From JAK2 V617F to a Mutated Chaperone - Prof Stef
 an Constantinescu (Head\, Signal Transduction & Molecular Hematology Unit\
 , Ludwig Institute for Cancer Research\, Brussels\, Belgium)
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