Expression of thrombopoietin receptor and its functional role in human B-precursor leukemia cells with 11q23 translocation or Philadelphia chromosome.
Thrombopoietin (TPO) is a hematopoietic growth factor which plays a central role in normal megakaryocytopoiesis and thrombopoiesis. Although the interaction between TPO and its receptor c-Mpl encoded by the c-mpl gene is now known to be implicated in the proliferation and/or differentiation of abnormal myeloid cells and normal hematopoietic stem cells, little is known about a role of the TPO/c-Mpl system in lymphoid leukemia cells. In the present study, we first examined the expression of c-mpl/c-Mpl in 23 human lymphoid leukemic cell lines (T-lineage 4, B-lineage 19) using three distinct methods. The c-mpl mRNA was detectable in as many as 20 cell lines (T-lineage 3, B-lineage 17) by reverse transcriptase-polymerase chain reaction, but its translated product, c-Mpl, was demonstrable by Western blot only in B-lineage cell lines. Flow cytometric analysis revealed the surface c-Mpl expression in 13 of 17 B-lineage cell lines, but its higher expression (>40%) was restricted in nine B-precursor cell lines, eight of which had 11q23 translocation or Philadelphia chromosome (Ph1). We also demonstrated that two of eight cell lines with 11q23 translocation or Ph1 exhibited a significant proliferative response to TPO in the 3H-thymidine uptake and colony-forming assays. Triggering of these cell lines by TPO transiently up-regulated tyrosine phosphorylation of JAK-2 and Shc, indicating that their receptor is functional. Primary leukemia cells separated from patients with B-precursor acute lymphoblastic leukemia with Ph1 or 11q23 translocation also showed the surface c-Mpl expression and a significant responsiveness to TPO. These results suggest that the TPO/c-Mpl interaction may play a physiological role in the growth regulation of B-precursor leukemia cells particularly with specific chromosomal abnormalities.
Iijima
K
K
Department of Pediatrics, Yamanashi Medical University, Japan.
Sugita
K
K
Inukai
T
T
Goi
K
K
Tezuka
T
T
Uno
K
K
Sato
H
H
Kagami
K
K
Nakazawa
S
S
D000954:Antigens, Surface / Q000096:biosynthesis; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D004247:DNA / Q000096:biosynthesis; D015870:Gene Expression; D006801:Humans; D007945:Leukemia, Lymphoid / Q000235:genetics* / Q000378:metabolism; D009363:Neoplasm Proteins; D010677:Philadelphia Chromosome; D010766:Phosphorylation; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014178:Translocation, Genetic; D014316:Tritium; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay; D014443:Tyrosine / Q000378:metabolism
D000954:Antigens, Surface; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D053628:Receptors, Thrombopoietin; D014316:Tritium; C082218:MPL protein, human; D014443:Tyrosine; D004247:DNA; D013926:Thrombopoietin; D013936:Thymidine