Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1α but negatively regulates marrow homing in vivo

Seiji Fukuda, Louis Pelus

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objective: We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1α/CXCR4 signaling pathway. Herein, we evaluated whether a functional interaction between SDF1α/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hematopoietic survival. We also investigated molecular mechanisms responsible for enhanced migration to SDF1α as a result of ITD-Flt3 expression and whether ITD-Flt3 regulates hematopoietic cell trafficking. Methods: Hematopoietic progenitor cell survival was determined using marrow cells retrovirally expressing ITD-Flt3 and stimulated with SDF1α. Migration, to SDF1α adhesion to vascular cell adhesion molecule-1, and in vivo homing were determined using Ba/F3 cells expressing ITD-Flt3 and transfected with dominant negative (DN) H-Ras. Results: Addition of SDF1α significantly increased growth factor-independent proliferation of colony-forming unit granulocyte-macrophage induced by ITD-Flt3. Although a negative gradient of SDF1α inhibited migration regardless of the stimulation, a positive gradient of FL or ITD-Flt3 significantly increased cell migration even in the presence of a negative SDF1α gradient. Enhanced migration induced by ITD-Flt3 was inhibited by DN-H-Ras, whereas overexpression of a constitutive active form of H-Ras in wild-type Flt3-Ba/F3 cells significantly elevated migration to SDF1α. Despite enhanced migration to SDF1α, preincubation with FL or ITD-Flt3 overexpression significantly reduced homing of primary mouse bone marrow cells or Ba/F3 cells to bone marrow that was associated with significant reduction in adhesion to vascular cell adhesion molecule-1 and VLA4 expression. Conclusion: Our results suggest that functional interactions between Flt3 and SDF1α/CXCR4 regulate oncogenic proliferation and migration of hematopoietic cells, which is mediated by Ras, and that Flt3 signaling regulates hematopoietic cell trafficking in vivo.

Original languageEnglish
Pages (from-to)1041-1051
Number of pages11
JournalExperimental Hematology
Volume34
Issue number8
DOIs
StatePublished - Aug 2006

Fingerprint

Chemotaxis
Cell Survival
Bone Marrow
Cell Movement
Vascular Cell Adhesion Molecule-1
Bone Marrow Cells
Granulocyte-Macrophage Progenitor Cells
Hematopoietic Stem Cells
Intercellular Signaling Peptides and Proteins
flt3 ligand protein

ASJC Scopus subject areas

  • Cancer Research
  • Cell Biology
  • Genetics
  • Hematology
  • Oncology
  • Transplantation

Cite this

Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1α but negatively regulates marrow homing in vivo. / Fukuda, Seiji; Pelus, Louis.

In: Experimental Hematology, Vol. 34, No. 8, 08.2006, p. 1041-1051.

Research output: Contribution to journalArticle

@article{54411b9baff04878bc5d0aab8f4c8e3a,
title = "Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1α but negatively regulates marrow homing in vivo",
abstract = "Objective: We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1α/CXCR4 signaling pathway. Herein, we evaluated whether a functional interaction between SDF1α/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hematopoietic survival. We also investigated molecular mechanisms responsible for enhanced migration to SDF1α as a result of ITD-Flt3 expression and whether ITD-Flt3 regulates hematopoietic cell trafficking. Methods: Hematopoietic progenitor cell survival was determined using marrow cells retrovirally expressing ITD-Flt3 and stimulated with SDF1α. Migration, to SDF1α adhesion to vascular cell adhesion molecule-1, and in vivo homing were determined using Ba/F3 cells expressing ITD-Flt3 and transfected with dominant negative (DN) H-Ras. Results: Addition of SDF1α significantly increased growth factor-independent proliferation of colony-forming unit granulocyte-macrophage induced by ITD-Flt3. Although a negative gradient of SDF1α inhibited migration regardless of the stimulation, a positive gradient of FL or ITD-Flt3 significantly increased cell migration even in the presence of a negative SDF1α gradient. Enhanced migration induced by ITD-Flt3 was inhibited by DN-H-Ras, whereas overexpression of a constitutive active form of H-Ras in wild-type Flt3-Ba/F3 cells significantly elevated migration to SDF1α. Despite enhanced migration to SDF1α, preincubation with FL or ITD-Flt3 overexpression significantly reduced homing of primary mouse bone marrow cells or Ba/F3 cells to bone marrow that was associated with significant reduction in adhesion to vascular cell adhesion molecule-1 and VLA4 expression. Conclusion: Our results suggest that functional interactions between Flt3 and SDF1α/CXCR4 regulate oncogenic proliferation and migration of hematopoietic cells, which is mediated by Ras, and that Flt3 signaling regulates hematopoietic cell trafficking in vivo.",
author = "Seiji Fukuda and Louis Pelus",
year = "2006",
month = "8",
doi = "10.1016/j.exphem.2006.04.001",
language = "English",
volume = "34",
pages = "1041--1051",
journal = "Experimental Hematology",
issn = "0301-472X",
publisher = "Elsevier Inc.",
number = "8",

}

TY - JOUR

T1 - Internal tandem duplication of Flt3 modulates chemotaxis and survival of hematopoietic cells by SDF1α but negatively regulates marrow homing in vivo

AU - Fukuda, Seiji

AU - Pelus, Louis

PY - 2006/8

Y1 - 2006/8

N2 - Objective: We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1α/CXCR4 signaling pathway. Herein, we evaluated whether a functional interaction between SDF1α/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hematopoietic survival. We also investigated molecular mechanisms responsible for enhanced migration to SDF1α as a result of ITD-Flt3 expression and whether ITD-Flt3 regulates hematopoietic cell trafficking. Methods: Hematopoietic progenitor cell survival was determined using marrow cells retrovirally expressing ITD-Flt3 and stimulated with SDF1α. Migration, to SDF1α adhesion to vascular cell adhesion molecule-1, and in vivo homing were determined using Ba/F3 cells expressing ITD-Flt3 and transfected with dominant negative (DN) H-Ras. Results: Addition of SDF1α significantly increased growth factor-independent proliferation of colony-forming unit granulocyte-macrophage induced by ITD-Flt3. Although a negative gradient of SDF1α inhibited migration regardless of the stimulation, a positive gradient of FL or ITD-Flt3 significantly increased cell migration even in the presence of a negative SDF1α gradient. Enhanced migration induced by ITD-Flt3 was inhibited by DN-H-Ras, whereas overexpression of a constitutive active form of H-Ras in wild-type Flt3-Ba/F3 cells significantly elevated migration to SDF1α. Despite enhanced migration to SDF1α, preincubation with FL or ITD-Flt3 overexpression significantly reduced homing of primary mouse bone marrow cells or Ba/F3 cells to bone marrow that was associated with significant reduction in adhesion to vascular cell adhesion molecule-1 and VLA4 expression. Conclusion: Our results suggest that functional interactions between Flt3 and SDF1α/CXCR4 regulate oncogenic proliferation and migration of hematopoietic cells, which is mediated by Ras, and that Flt3 signaling regulates hematopoietic cell trafficking in vivo.

AB - Objective: We have previously shown that Flt3 ligand (FL)/Flt3 signaling regulates hematopoietic cell migration by modulating the SDF1α/CXCR4 signaling pathway. Herein, we evaluated whether a functional interaction between SDF1α/CXCR4 signaling and internal tandem duplication (ITD) of Flt3 regulates aberrant hematopoietic survival. We also investigated molecular mechanisms responsible for enhanced migration to SDF1α as a result of ITD-Flt3 expression and whether ITD-Flt3 regulates hematopoietic cell trafficking. Methods: Hematopoietic progenitor cell survival was determined using marrow cells retrovirally expressing ITD-Flt3 and stimulated with SDF1α. Migration, to SDF1α adhesion to vascular cell adhesion molecule-1, and in vivo homing were determined using Ba/F3 cells expressing ITD-Flt3 and transfected with dominant negative (DN) H-Ras. Results: Addition of SDF1α significantly increased growth factor-independent proliferation of colony-forming unit granulocyte-macrophage induced by ITD-Flt3. Although a negative gradient of SDF1α inhibited migration regardless of the stimulation, a positive gradient of FL or ITD-Flt3 significantly increased cell migration even in the presence of a negative SDF1α gradient. Enhanced migration induced by ITD-Flt3 was inhibited by DN-H-Ras, whereas overexpression of a constitutive active form of H-Ras in wild-type Flt3-Ba/F3 cells significantly elevated migration to SDF1α. Despite enhanced migration to SDF1α, preincubation with FL or ITD-Flt3 overexpression significantly reduced homing of primary mouse bone marrow cells or Ba/F3 cells to bone marrow that was associated with significant reduction in adhesion to vascular cell adhesion molecule-1 and VLA4 expression. Conclusion: Our results suggest that functional interactions between Flt3 and SDF1α/CXCR4 regulate oncogenic proliferation and migration of hematopoietic cells, which is mediated by Ras, and that Flt3 signaling regulates hematopoietic cell trafficking in vivo.

UR - http://www.scopus.com/inward/record.url?scp=33746086336&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33746086336&partnerID=8YFLogxK

U2 - 10.1016/j.exphem.2006.04.001

DO - 10.1016/j.exphem.2006.04.001

M3 - Article

C2 - 16863910

AN - SCOPUS:33746086336

VL - 34

SP - 1041

EP - 1051

JO - Experimental Hematology

JF - Experimental Hematology

SN - 0301-472X

IS - 8

ER -