Transforming growth factor-beta1 sensitivity is altered in Abl-Myc- and Raf-Myc-induced mouse pre-B-cell tumors.
Understanding the mechanisms leading to transformation of early B-lineage precursors is an important step leading to rational design of new treatments for precursor (pre)-B-cell leukemia. We used normal mouse pre-B cells to determine if and how transforming growth factor (TGF)-beta1 affects these precursors to the B-cell lineage and whether transformed pre-B cells respond to TGF-beta1. We found that normal pre-B cells proliferating in the presence of interleukin (IL)-7 enter cell-cycle arrest after exposure to TGF-beta1. However, clonally related IL-7-independent tumors induced by oncogenes abl + myc or raf + myc have reduced sensitivity to TGF-beta1. In contrast, tumor cells induced by myc alone remain sensitive to TGF-beta1 growth suppression. These results suggest that lesions in different molecular signaling pathways can lead to loss of TGF-beta1 sensitivity in a single cell type. The approach of using normal pre-B-cell lines and transformation by overexpression of different oncogenes provides a system to compare and contrast molecular pathways that lead to full malignancy.
Letterio
John
J
Case Western Reserve University, Division of Pediatric Hematology/Oncology, The Ireland Cancer Center, Cleveland, Ohio, USA.
Rudikoff
Eva
E
Voong
Nga
N
Bauer
Steven R
SR
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic; D016193:G1 Phase / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000473:pathology*; D016274:Oncogene Protein p55(v-myc) / Q000235:genetics* / Q000378:metabolism; D016374:Oncogene Proteins v-abl / Q000235:genetics* / Q000378:metabolism; D027384:Oncogene Proteins v-raf / Q000235:genetics* / Q000378:metabolism; D020395:Receptors, Interleukin-7 / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
D016274:Oncogene Protein p55(v-myc); D016374:Oncogene Proteins v-abl; D020395:Receptors, Interleukin-7; D053773:Transforming Growth Factor beta1; D027384:Oncogene Proteins v-raf