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Inhibition of MLL-Menin interaction by small peptide molecules: a new investigation way and a possible therapeutic tool

Targeting MLL interacting domains in MLL­‐associated leukemia could be a innovative therapeutic approach. In this study, we report the development of a protein­‐based method of delivery of MLL domains into leukemia cells. In according with this method we independently fused the hMBM domain to the 11 aminoacids of the TAT-­‐PTD. We investigated if recombinant TAT proteins can efficiently penetrate into the cell impairing cell growth, cell viability and/or differentiation of cells, harboring MLL fusion proteins. We provide evidence that these TAT­‐fragments can differently and selectively inhibit MLL fusion protein interactions, without interfering with wild type form. Preliminary studies indicate TAT-­hMBM as a good potential therapeutic agent to target MLL­‐fusion protein interactions, because it is small and very selective. The small TAT‐fragments enter leukemia cells reverting, at last, the leukemia phenotype.
These results encourage the development of small interfering peptide molecules. So we study and optimize an in vitro system to reproduce menin-­‐MLL in vivo interaction and to describe how TAT­‐hMBM competes with MLL to interact with menin. Using this assay we tested a pool of small peptide molecule designed on the portion of MLL involved in interacting with Menin. We found that some small peptide molecule are able to inhibit the Menin‐MLL interaction better than others and we started from this to study another molecule designed on the best candidate from the precendent test.

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    10     1.1.HEMATOPOIESIS   Hematopoiesis  is   an  highly  orchestrated   process  by  which  immature  precursor  cells   develop  into  new  mature   blood  cells,  which  includes  red  blood  cells  ( erythrocytes),   white  blood  cells  ( leukocytes),  and  platelets  (Orkin  et  al.  1995,  1996).  It  begins  early  in   embryonic  development  and  continues  throughout  the  lifetime  of  an  organism.   In  developing  embryos,  blood   formation  occurs  in  aggregates  of  blood  cells  in  the  yolk   sac.  When  bone  marrow  develops,  it,  with  its  intersinusoidal  spaces,  assumes  the  task  of   forming  most  of  the  blood  cells  for  the  entire  organism.  However,  maturation,   activation,  and  some  prolifera tion  of  lymphoid  cells  occurs  in  secondary  lymphoid   organs  (spleen,  thymus,  and  lymph  nodes).  In  children,  haematopoiesis  occurs  in  the   marrow  of  the  long  bones,  in  adults,  it  occurs  mainly  in  the  pelvis,  cranium,  vertebrae,   and  sternum.   The  sinusoids   (venous  channels)  feed  into  the  marrow  venous  drainage  system,  they  are   lined  with  specialized  fenestrated  endothelial  cells.  These  cells  produce  growth  factors   and  cytokines,  which  influence  proliferation  and  differentiation  of  hematopoietic  cells   and  thu s  play  an  important  regulatory  role.  Mature  blood  cells  enter  the  blood  stream   by   passing  through  the  sinusoidal  wall  to  get  into  the  sinuses.  The  bone  marrow  stroma   contains  many  different  cell  types,  including  macrophages,  fibroblasts,  endothelial  cells,   smooth  muscle  cells,  T -­‐lymphocytes,  monocytes.  These  cells,  in  combination  with   components  of  the  extracellular  matrix  and  basement  membranes  as  well  as  a  plethora   of  soluble  and  membrane -­‐bound  cytokines  and  growth  factor,  form  the  so -­‐called   Hematopoietic  inductive  microenvironment   (HIM),  which  maintains  the  functional   integrity  of  this  complex  system  of  resident  and  circulating  cells.  (Trentin,  JJ.  1971)   All  different  types  of  blood  cells  are  derived  from  a  small  common  pool  of  totipotent   cells,  called  hematopoietic  stem  cells  (HSCs).  These  cells  have  the  unique  properties  to   give  rise  to  new  hematopoietic  stem  cells  (self -­‐renewal)  and  generate  primitive   progenitors  that  are  programmed  to  differentiate.  This  process  is  called   Steady-­‐ state   hematopoiesis   or  Constitutive  hematopoiesis .   During  or  after  cell  division  the  two  daughter  cells  of  a  HSC  have  to  decide  their  fate.  

Tesi di Dottorato

Dipartimento: Dipartimento di medicina Clinica e Sperimentale

Autore: Riccardo Panella Contatta »

Composta da 185 pagine.

 

Questa tesi ha raggiunto 489 click dal 20/03/2013.

Disponibile in PDF, la consultazione è esclusivamente in formato digitale.