2-10-10 Molecular and Immunologic Markers of Hematologic Neoplasia 1.

Describe the structure of the human genome as containing approximately 3 billion base pairs, and 25,000-30,000 genes. Only a small number of genes called oncogenes and tumor suppressor genes have been implicated in neoplasia Multiple mutations are necessary for transformation 2. Define leukemias or lymphomas as genetically altered clonal expansions. Neoplasia arises from either uncontrolled proliferation or resistance to apoptosis! and is often sub"ect to #maturation arrest$ In other %ords! the neoplastic cells are stuck in some specific phase in the normal path%ay of differentiation Neoplastic cells are classified by morphology &gold standard'! protein! and (N) profiles 3. tate the mechanisms in!ol!ed in the chromosomal translocations of follicular lymphoma, "urkitt lymphoma, #$%, and &'% and describe ho( these translocations are used to help diagnose or treat these diseases. )ll chromosomal translocations arise from *&+', recombination of Ig and -.(s )ollicular #enter " #ell %ymphoma/ t&10112' #3our 3ollicular$causes 405 cases of 36 -he translocation upregulates Bcl-2 &by moving it closer to enhancers on IgH'! an anti-apoptotic gene -his makes the lymphoma cells resistant to apoptosis1 thus! 36 is a disease of accumulation "urkitt %ymphoma/ t&2110' #2 looks a lot like 7$ translocation elevates c-myc &by moving it closer to enhancers on IgH'! %hich is an oncogene -his makes the lymphoma cells proliferate #$%/ t&4121' #my nine$ has 1005 specificity for .M61 this #8hiladelphia chromosome$ translocation produces the BCR(9)-ABL(21) fusion protein that increases oncogene tyrosine kinase activity! thus increasing proliferation &'% &aka )M6-M9'/ t&1:11;' causes the PML(15)-RAR(17) fusion protein &aka p2107.(-)76' that has increased affinity for +N)! binding and disrupting e<pression for granulocyte synthesis &this is a #dominant negative$ translocation' -he fusion protein is dependent on retinoic acid for function! so )-() can be specifically targeted against )86 cells *. tate the t(o mechanisms by (hich chromosomal translocations result in abnormal gene expression, and (hy chimeric proteins are such good potential therapeutic targets. 1' #gain of function$ mutation %here an oncogene gets translocated near an enhancer! increasing its e<pression and &thus' proliferation

2' #disease of accumulation$ mutation %here anti-apoptotic genes are translocated ne<t to enhancers! blocking apoptosis .himeric proteins like 8M6=()( in acute promyelocytic leukemia allo% for specific drug targeting 5. tate the most sensiti!e method to detect minimal residual disease. -he most sensitive method to detect lo% numbers of residual neoplastic cells &so called minimal residual disease >M(+?' is 8.( 8.( techni@ues can detect as fe% as 1 neoplastic cell among 100!000 normal cells