title: Functional CXCR4-expressing microparticles and SDF-1 correlate with circulating acute myelogenous leukemia cells.
abstract: Stromal cell-derived factor-1 (SDF-1/CXCL12) and its receptor CXCR4 are implicated in the pathogenesis and prognosis of acute myelogenous leukemia (AML). Cellular microparticles, submicron vesicles shed from the plasma membrane of various cells, are also associated with human pathology. In the present study, we investigated the putative relationships between the SDF-1/CXCR4 axis and microparticles in AML. We detected CXCR4-expressing microparticles (CXCR4(+) microparticles) in the peripheral blood and bone marrow plasma samples of normal donors and newly diagnosed adult AML patients. In samples from AML patients, levels of CXCR4(+) microparticles and total SDF-1 were elevated compared with normal individuals. The majority of CXCR4(+) microparticles in AML patients were CD45(+), whereas in normal individuals, they were mostly CD41(+). Importantly, we found a strong correlation between the levels of CXCR4(+) microparticle and WBC count in the peripheral blood and bone marrow plasma obtained from the AML patients. Of interest, levels of functional, noncleaved SDF-1 were reduced in these patients compared with normal individuals and also strongly correlated with the WBC count. Furthermore, our data indicate NH(2)-terminal truncation of the CXCR4 molecule in the microparticles of AML patients. However, such microparticles were capable of transferring the CXCR4 molecule to AML-derived HL-60 cells, enhancing their migration to SDF-1 in vitro and increasing their homing to the bone marrow of irradiated NOD/SCID/beta2m(null) mice. The CXCR4 antagonist AMD3100 reduced these effects. Our findings suggest that functional CXCR4(+) microparticles and SDF-1 are involved in the progression of AML. We propose that their levels are potentially valuable as an additional diagnostic AML variable.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Sigal
authors.initials: S
authors.lastname: Tavor
authors.forename: Abraham
authors.initials: A
authors.lastname: Avigdor
authors.forename: Joy
authors.initials: J
authors.lastname: Kahn
authors.forename: Alexander
authors.initials: A
authors.lastname: Brill
authors.forename: Isabelle
authors.initials: I
authors.lastname: Petit
authors.forename: Polina
authors.initials: P
authors.lastname: Goichberg
authors.forename: Melania
authors.initials: M
authors.lastname: Tesio
authors.forename: Neta
authors.initials: N
authors.lastname: Netzer
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Naparstek
authors.forename: Izhar
authors.initials: I
authors.lastname: Hardan
authors.forename: Arnon
authors.initials: A
authors.lastname: Nagler
authors.forename: Igor
authors.initials: I
authors.lastname: Resnick
authors.forename: Alexander
authors.initials: A
authors.lastname: Tsimanis
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001853:Bone Marrow / Q000378:metabolism; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000097:blood*; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000097:blood* / Q000473:pathology; D007958:Leukocyte Count; D008297:Male; D008875:Middle Aged; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000097:blood*; D020298:U937 Cells
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D019718:Receptors, CXCR4