Induction of polyploidization in leukemic cell lines and primary bone marrow by Src kinase inhibitor SU6656.
Megakaryocytes (MKs) undergo successive rounds of endomitosis during differentiation, resulting in polyploidy (typically, 16-64N). Previous studies have demonstrated that this occurs through an interruption of normal cell cycle progression during anaphase. However, the molecular mechanism(s) controlling this unique process is undefined. In the present report, we examine the effect of an Src kinase inhibitor, SU6656, on thrombopoietin (TPO)-induced growth and differentiation. Remarkably, when SU6656 (2.5 microM) was added to a megakaryocytic cell line, UT-7/TPO, the cells ceased cell division but continued to accumulate DNA by endomitosis. During this interval, CD41 and CD61 expression on the cell surface increased. Similar effects on polyploidization and MK differentiation were seen with expanded primary MKs, bone marrow from 2 patients with myelodysplastic syndrome, and other cell lines with MK potential. Our data suggest that SU6656 might be useful as a differentiation-inducing agent for MKs and is an important tool for understanding the molecular basis of MK endomitosis.
Lannutti
Brian J
BJ
Puget Sound Blood Center, 921 Terry Ave, Seattle, WA 98104, USA. brianl@psbc.org
Blake
Noel
N
Gandhi
Manish J
MJ
Reems
Jo Anna
JA
Drachman
Jonathan G
JG
D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D007938:Leukemia / Q000235:genetics* / Q000473:pathology; D008533:Megakaryocytes / Q000187:drug effects / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000473:pathology; D011123:Polyploidy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*; D019061:src-Family Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D007211:Indoles; D047428:Protein Kinase Inhibitors; C416927:SU 6656; D013449:Sulfonamides; D019061:src-Family Kinases