RT Book, Section
A1 Thomas Look, A.
A2 Valle, David L.
A2 Antonarakis, Stylianos
A2 Ballabio, Andrea
A2 Beaudet, Arthur L.
A2 Mitchell, Grant A.
SR Print(0)
ID 1181403812
T1 Genes Altered by Chromosomal Translocations in Leukemias and Lymphomas
T2 The Online Metabolic and Molecular Bases of Inherited Disease
YR 2019
FD 2019
PB McGraw-Hill Education
PP New York, NY
SN 9780071459969
LK ommbid.mhmedical.com/content.aspx?aid=1181403812
RD 2024/04/19
AB Somatically  acquired  chromosomal  translocations  activate  proto-oncogenes  in  the  hematopoietic  cells  of  both  children  and  adults.  This  mechanism  of  gene  dysregulation  contributes  to  well  over  50  percent  of  all  leukemias  that  have  been  characterized  cytogenetically  and  molecularly  and  to  a  substantial  proportion  of  lymphomas,  notably  the  Burkitt,  large-cell,  and  follicular  types.In  most  instances,  chromosomal  translocations  fuse  sequences  of  a  transcription  factor  or  receptor  tyrosine  kinase  gene  to  those  of  a  normally  unrelated  gene,  resulting  in  a  chimeric  protein  with  oncogenic  properties.  Repositioning  of  transcriptional  control  genes  to  the  vicinity  of  highly  active  promoter/enhancer  elements,  such  as  those  associated  with  immunoglobulin  or  T-cell  receptor  genes,  is  a  second  mechanism  by  which  chromosomal  translocations  induce  malignancy.The  vast  majority  of  translocation-induced  leukemias  and  lymphomas  are  restricted  to  cells  of  a  single  lineage  arrested  at  a  particular  stage  of  development,  indicating  that  the  disrupted  genes  regulate  vital  processes  limited  to  a  subset  of  committed  hematopoietic  progenitors.  Occasionally,  as  exemplified  by  leukemias  arising  from  MLL  gene  abnormalities,  more  than  one  lineage  or  developmental  stage  is  affected,  suggesting  the  involvement  of  genes  active  in  pluripotent  or  bipotent  stem  cells.The  number  of  fusion  genes  with  diagnostic  and  prognostic  relevance  is  increasing  rapidly.  The  hybrid  mRNAs  produced  by  these  novel  structures  provide  specific  molecular  probes  for  identifying  affected  patients  who  cannot  be  diagnosed  readily  by  conventional  means  or  who  require  chemotherapy  tailored  to  the  risk  conferred  by  a  particular  genetic  lesion.Studies  in  murine  models,  in  which  specific  genes  are  mutated  and  homozygously  inactivated  in  “knockout”  mice  or  overexpressed  in  transgenic  mice,  have  contributed  new  insights  into  the  essential  roles  that  are  played  in  normal  development  and  oncogenesis  by  genes  discovered  because  of  their  proximity  to  the  breakpoints  of  chromosomal  translocations  in  the  human  leukemias  and  lymphomas.