HO-1 inhibits migration of leukemic cells

The complement cascade (ComC) is a crucial element of innate immunity and is involved in several processes related to fighting infection by releasing active mediators, including C3a and desArgC3a, which result from cleavage of complement component 3 (C3), and C5a and desArgC5a, which result from cleavage of complement component 5 (C5) [1-3]. In parallel, evidence has accumulated that, in addition to their immunological functions, ComC cleavage fragments modulate stem cell migration during organogenesis [2]. The ComC also orchestrates the egress of normal hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM) into peripheral blood (PB) in a process known as mobilization and mediates homing and engraftment of HSPCs in hematopoietic organs after transplantation [3]. Interestingly, these pro-mobilization and pro-homing effects are indirect, as they involve other cells in the hematopoietic microenvironment. For example, although HSPCs express the functional C5a receptor (C5aR, also known as CD88), and respond to stimulation by C3a, surprisingly these cells do not show spontaneous chemotaxis in response to C3a, C5a, desArgC3a, or desArgC5a [3]. In contrast, all these C3 and C5 cleavage fragments promote migration of already differentiated hematopoietic cells, including granulocytes, monocytes, lymphocytes, and NK cells [1-3]. On the other hand, the ComC plays a role in the pathogenesis of several solid tumors by modifying tumor cell growth, while affecting metastatic potential and the response to therapeutics [2, 4-7]. Nevertheless, in contrast to solid tumors, the potential involvement of the ComC in leukemia has not been studied extensively. To fill in this knowledge gap, we asked whether human leukemia cell lines and primary patient leukemic blasts express functional C3 and C5 cleavage-fragment receptors (C3aR and C5aR, respectively) and whether activation of the ComC and release of C3a and C5a anaphylatoxins affects the biology of leukemic cells [1]. This question was prompted by our hypothesis that infections accompanying leukemia and/or the application of chemotherapy in leukemic patients trigger activation of the ComC and the release of potent mediators derived from C3 and C5 cleavage. In our experiments we employed several established human myeloid and lymphoma cell lines, purified CD33+ blasts from leukemia patients, and studied the effect of C3a, C5a, desArgC3a, and desArgC5a on the proliferation, survival, migration, and adhesion of these cells [1]. Interestingly, we found that human leukemia cell lines as well as clonogenic blasts from CML and AML patients express C3aand C5a-binding receptors at the mRNA (RT-PCR) and protein (FACS) levels, and these receptors respond to C3a and C5a stimulation by phosphorylation of p42/44 and p38 MAPK and AKT. We also observed that, while C3 and C5 cleavage fragments did not stimulate proliferation of leukemic cells, they induced random motility (chemokinesis) of these cells Editorial