Thursday, February 28, 2013

PART II  TARGET THERAPY IN AML (ACUTE MYELOID LEUKEMIA)
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If you dismissed the discussion about core binding factor (CBF), or raise your eyebrows in a sign of not being impressed by the information, just you wait for a second.  Because things get complicated very fast.  By now you grasp the notion of the CBF, and know that overall the CBF involvement is of good prognosis.
But if you recall, the CBF seems to have at least 2 subunits. one alpha reportedly attached to a DNA or Gene substrate and one swimming and interacting with Histone and surrounding molecules.  We discussed that over all the CBF act as Histone DeaCetylase Inhibitor but we also added that through this effect, CBF affects Ribosome, transcription factors and and various genes as well upstream retrograde or feedback effect on ubiquitination, signal induction pathways, and on mitochondria.

The tentacles from CBF will create an effect that depends on the nature of the surrounding molecule.
focusing on good prognosis AML, through direct interaction or through Ribosomal or gene contact effect, CBF could trigger MYCN amplification. As opposed to c-MYC, globally MYCN, a member of the MYC family that maps to the short arm of chromosome 2 at band 2p24, is considered a good prognosis in any proliferative disease.  Should CBF activity lead to MYCN amplification directly or through overexpression of miR17-92 (with ribosomal location), at least 8 consequences results:

1.Overexpression of CDK4  (Cyclin dependent kinase 4) which phosphorylate RB-1 and stops the cell cycle in G-1.  Remember p16ink 4a is its inhibitor (Melanoma).   Therefore MYCN stops proliferation!  That's why its a good prognostic factor!

2.  Overexpression of RSG2 ( G protein regulator) mostly with inhibitory membrane and submembrane activity effects affecting cell division  as well as angiogenesis, again good for you!

3.Overexpression of MDM2, a ubiquitination ligase of P53.  In Leukemia, proliferation will be exacerbated by this action (not so good for us! but inhibitors could prove good target therapy) 
  (To be continued)
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