Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein.
Mice deficient for the transcription factor, interferon consensus sequence binding protein (ICSBP), are immunodeficient and develop disease symptoms similar to human chronic myeloid leukemia (CML). To elucidate the hematopoietic disorder of ICSBP(-/-) mice, we investigated the growth, differentiation, and leukemogenic potential of ICSBP(-/-) myeloid progenitor cells in vitro, as well as by cell-transfers in vivo. We report that adult bone marrow, as well as fetal liver of ICSBP-deficient mice harbor increased numbers of progenitor cells, which are hyperresponsive to both granulocyte macrophage colony-stimulating factor (GM-CSF) and G-CSF in vitro. In contrast, their response to M-CSF is strongly reduced and, surprisingly, ICSBP(-/-) colonies formed in the presence of M-CSF are mostly of granulocytic morphology. This disproportional differentiation toward cells of the granulocytic lineage in vitro parallels the expansion of granulocytes in ICSBP(-/-) mice and correlates with a 4-fold reduction of M-CSF receptor expressing cells in bone marrow. Cell transfer studies showed an intrinsic leukemogenic potential and long-term reconstitution capability of ICSBP(-/-) progenitors. Further experiments demonstrated strongly reduced adhesion of colony-forming cells from ICSBP(-/-) bone marrow to fibronectin. In summary, ICSBP(-/-) myeloid progenitor cells share several abnormal features with CML progenitors, suggesting that the distal parts of signaling pathways of these two disorders are overlapping.
Scheller
M
M
Abteilung für Molekulare Genetik, Forschungsinstitut für Molekulare Pharmakologie, und Universitätsklinikum Benjamin Franklin, Freie Universität Berlin, Berlin, Germany.
Foerster
J
J
Heyworth
C M
CM
Waring
J F
JF
Löhler
J
J
Gilmore
G L
GL
Shadduck
R K
RK
Dexter
T M
TM
Horak
I
I
D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology / Q000502:physiology; D005786:Gene Expression Regulation; D015972:Gene Expression Regulation, Neoplastic; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D006801:Humans; D050835:Interferon Regulatory Factors; D007372:Interferons / Q000235:genetics; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics; D019891:Leukopoiesis / Q000235:genetics; D051379:Mice; D012097:Repressor Proteins / Q000235:genetics*; D000099185:Interferon Regulatory Factor-8
D016207:Cytokines; D050835:Interferon Regulatory Factors; D007372:Interferons; D012097:Repressor Proteins; D000099185:Interferon Regulatory Factor-8