Further evidence that paroxysmal nocturnal haemoglobinuria is a disorder of
defective cell membrane lipid rafts
#MMPMID26033571
Ratajczak MZ
; Borkowska S
; Mierzejewska K
; Kucia M
; Mendek-Czajkowska E
; Suszynska M
; Sharma VA
; Deptala A
; Song W
; Platzbecker U
; Larratt L
; Janowska-Wieczorek A
; Maciejewski J
; Ratajczak J
J Cell Mol Med
2015[Sep]; 19
(9
): 2193-201
PMID26033571
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The glycolipid glycosylphosphatidylinositol anchor (GPI-A) plays an important
role in lipid raft formation, which is required for proper expression on the cell
surface of two inhibitors of the complement cascade, CD55 and CD59. The absence
of these markers from the surface of blood cells, including erythrocytes, makes
the cells susceptible to complement lysis, as seen in patients suffering from
paroxysmal nocturnal haemoglobinuria (PNH). However, the explanation for why
PNH-affected hematopoietic stem/progenitor cells (HSPCs) expand over time in BM
is still unclear. Here, we propose an explanation for this phenomenon and provide
evidence that a defect in lipid raft formation in HSPCs leads to defective CXCR4-
and VLA-4-mediated retention of these cells in BM. In support of this
possibility, BM-isolated CD34(+) cells from PNH patients show a defect in the
incorporation of CXCR4 and VLA-4 into membrane lipid rafts, respond weakly to
SDF-1 stimulation, and show defective adhesion to fibronectin. Similar data were
obtained with the GPI-A(-) Jurkat cell line. Moreover, we also report that
chimeric mice transplanted with CD55(-/-) CD59(-/-) BM cells but with proper
GPI-A expression do not expand over time in transplanted hosts. On the basis of
these findings, we propose that a defect in lipid raft formation in PNH-mutated
HSPCs makes these cells more mobile, so that they expand and out-compete normal
HSPCs from their BM niches over time.
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