Engagement of SIRP alpha Inhibits Growth and Induces Programmed Cell Death in Acute Myeloid Leukemia Cells

作者：Irandoust Mahban; Zarate Julian Alvarez; Hubeek Isabelle; van Beek Ellen M; Schornagel Karin; Broekhuizen Aart J F; Akyuz Mercan; van de Loosdrecht Arjan A; Delwel Ruud; Valk Peter J; Sonneveld Edwin; Kearns Pamela; Creutzig Ursula; Reinhardt Dirk; de Bont Eveline S J M; Coenen Eva A; van den Heuvel Eibrink Marry M; Zwaan C Michel; Kaspers Gertjan J L; Cloos Jacqueline; van den Berg Timo K^*

来源：PLos One, 2013, 8(1): e52143.

DOI：10.1371/journal.pone.0052143

Background: Recent studies show the importance of interactions between CD47 expressed on acute myeloid leukemia (AML) cells and the inhibitory immunoreceptor, signal regulatory protein-alpha (SIRP alpha) on macrophages. Although AML cells express SIRP alpha, its function has not been investigated in these cells. In this study we aimed to determine the role of the SIRP alpha in acute myeloid leukemia. %26lt;br%26gt;Design and Methods: We analyzed the expression of SIRP alpha, both on mRNA and protein level in AML patients and we further investigated whether the expression of SIRP alpha on two low SIRP alpha expressing AML cell lines could be upregulated upon differentiation of the cells. We determined the effect of chimeric SIRP alpha expression on tumor cell growth and programmed cell death by its triggering with an agonistic antibody in these cells. Moreover, we examined the efficacy of agonistic antibody in combination with established antileukemic drugs. %26lt;br%26gt;Results: By microarray analysis of an extensive cohort of primary AML samples, we demonstrated that SIRP alpha is differentially expressed in AML subgroups and its expression level is dependent on differentiation stage, with high levels in FAB M4/M5 AML and low levels in FAB M0-M3. Interestingly, AML patients with high SIRP alpha expression had a poor prognosis. Our results also showed that SIRP alpha is upregulated upon differentiation of NB4 and Kasumi cells. In addition, triggering of SIRP alpha with an agonistic antibody in the cells stably expressing chimeric SIRP alpha, led to inhibition of growth and induction of programmed cell death. Finally, the SIRP alpha-derived signaling synergized with the activity of established antileukemic drugs. %26lt;br%26gt;Conclusions: Our data indicate that triggering of SIRP alpha has antileukemic effect and may function as a potential therapeutic target in AML.

• 出版日期2013-1-8