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Articles by H. M Jack
Total Records ( 2 ) for H. M Jack
  A. B Eberle , K Herrmann , H. M Jack and O. Muhlemann
 

During B cell maturation, immunoglobulin (Ig) genes frequently acquire premature translation-termination codons (PTCs) as a result of the somatic rearrangement of V, D, and J gene segments. However, it is essential for a B lymphocyte to produce only one kind of antibody and therefore to ensure that the heavy and light chain polypeptides are expressed exclusively from the corresponding functional alleles, whereas no protein is made from the nonproductively rearranged alleles. At the post-transcriptional level, a well-studied mRNA quality control mechanism, termed nonsense-mediated mRNA decay (NMD), recognizes and degrades PTC-containing mRNAs in a translation-dependent manner. In addition, transcriptional silencing of PTC-containing Ig-µ and Ig- heavy chain reporter genes was observed in HeLa cells. To investigate the silencing of nonproductively rearranged Ig genes in a more physiological context, we analyzed a monoclonal line of immortalized murine pro-B cells harboring one productively (PTC–) and one nonproductively (PTC+) rearranged Ig-µ heavy chain allele. We show that the steady-state abundance of PTC+ mRNA was ~40-fold lower when compared to that of the PTC– mRNA. However, both the PTC+ and PTC– allele seemed to be equally well transcribed since the abundances of PTC+ and PTC– pre-mRNA were very similar and chromatin immunoprecipitations revealed comparable occupancy of RNA polymerase II and acetylated histone H3 on both alleles. Altogether, we found no evidence for transcriptional silencing of the PTC+ allele in this pro-B cell line; hence, the efficient down-regulation of the PTC+ Ig-µ mRNA results entirely from NMD.

  D Trageser , I Iacobucci , R Nahar , C Duy , G von Levetzow , L Klemm , E Park , W Schuh , T Gruber , S Herzog , Y. m Kim , W. K Hofmann , A Li , C. T Storlazzi , H. M Jack , J Groffen , G Martinelli , N Heisterkamp , H Jumaa and M. Muschen
 

B cell lineage acute lymphoblastic leukemia (ALL) arises in virtually all cases from B cell precursors that are arrested at pre–B cell receptor–dependent stages. The Philadelphia chromosome–positive (Ph+) subtype of ALL accounts for 25–30% of cases of adult ALL, has the most unfavorable clinical outcome among all ALL subtypes and is defined by the oncogenic BCR-ABL1 kinase and deletions of the IKAROS gene in >80% of cases. Here, we demonstrate that the pre–B cell receptor functions as a tumor suppressor upstream of IKAROS through induction of cell cycle arrest in Ph+ ALL cells. Pre–B cell receptor–mediated cell cycle arrest in Ph+ ALL cells critically depends on IKAROS function, and is reversed by coexpression of the dominant-negative IKAROS splice variant IK6. IKAROS also promotes tumor suppression through cooperation with downstream molecules of the pre–B cell receptor signaling pathway, even if expression of the pre–B cell receptor itself is compromised. In this case, IKAROS redirects oncogenic BCR-ABL1 tyrosine kinase signaling from SRC kinase-activation to SLP65, which functions as a critical tumor suppressor downstream of the pre–B cell receptor. These findings provide a rationale for the surprisingly high frequency of IKAROS deletions in Ph+ ALL and identify IKAROS-mediated cell cycle exit as the endpoint of an emerging pathway of pre–B cell receptor–mediated tumor suppression.

 
 
 
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