Differential effects of TGF-beta 1 on normal and leukemic human hematopoietic cell proliferation.
We evaluated the effects of transforming growth factor-beta 1 (TGF-beta 1) on the growth of hematopoietic progenitors in normal donors and in patients with hematologic malignancies now designed as clonal disorders of multipotential stem cells. TGF-beta 1 at 80 pM exhibited differential effects on the normal hematopoietic progenitors when cells were stimulated with different growth factors, such as G-CSF, GM-CSF, interleukin-3 (IL-3), or stem cell factor (SCF). The suppressive effect by TGF-beta 1 was increased for growth with GM-CSF, IL-3, and SCF, and growth with G-CSF was unaffected in hematologic malignancies, TGF-beta 1 suppression for growth with G-CSF was increased for essential thrombocythemia (ET) and polycythemia vera; chronic myelogenous leukemia (CML) in chronic phase; CML in accelerated phase; CML in myeloid crisis; myelodysplastic syndrome (MDS) in refractory anemia; MDS in refractory anemia with an excess of blasts; and acute myeloblastic leukemia (AML). In CML-myeloid crisis and AML, TGF-beta 1 almost completely abolished the growth, with some patient-to-patient variation. The mean ED50s for the growth of leukemic blast progenitors were 1.6, 1.2, 0.7, and 0.2 pM in the presence of G-CSF, GM-CSF, IL-3, and SCF, respectively, c-myc and c-myb antisense oligonucleotides significantly suppressed the growth of leukemic blast progenitors, but not that of clonogenic cells from normal donors and patients with ET. We also demonstrated that TGF-beta 1 inhibits mRNA expression by AML blasts for c-myc and/or c-myb. When the data are taken together, growth suppression by TGF-beta 1 appears to increase with the progression of clonal evolution in hematologic malignancies.
Murohashi
I
I
First Department of Internal Medicine, Saitama Medical School, Japan.
Endho
K
K
Nishida
S
S
Yoshida
S
S
Jinnai
I
I
Bessho
M
M
Hirashima
K
K
D001483:Base Sequence; D001752:Blast Crisis; D001853:Bone Marrow / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D015870:Gene Expression / Q000187:drug effects; D016259:Genes, myc; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology; D007377:Interleukin-3 / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000097:blood* / Q000473:pathology; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000473:pathology; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D009857:Oncogenes; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis*; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis*; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D012016:Reference Values; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D007377:Interleukin-3; D009838:Oligodeoxyribonucleotides; D011518:Proto-Oncogene Proteins; D020598:Proto-Oncogene Proteins c-myb; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D016179:Granulocyte Colony-Stimulating Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor