Biomedical Engineering Reference
In-Depth Information
h e use of arsenic trioxide in acute promyelocytic leukemia treatment
improved the clinical outcome of refractory or relapsed as well as newly diagnosed
acute promyelocytic leukemia. Arsenic trioxide at lower doses induces myeloid
dif erentiation, whereas in higher doses it induces apoptosis. Although ATRA and
arsenic trioxide are well tolerated, approximately one-fourth of the patients develop
dif erentiation syndrome, formerly known as retinoid acid syndrome. Symptoms
occur at er 2 to 21 d of treatment and are generally associated with increasing
white blood cell count and combined fever, weight gain, dyspnea, pleural ef usion,
and pulmonary ini ltrates on chest radiograph and, in some patients, renal failure,
hypotension, and pericardial ef usion. h e reported incidence of dif erentiation
syndrome ranges from 6% to 27%, with mortality rates varying from 1% to 7%
(Santos
et al
. 2004).
Dif erent reports have shown that leukocyte emigration from blood is a key
event in the development of dif erentiation syndrome. It depends on a sequential
cascade of leukocyte-endothelium interactions that are regulated by adhesion
molecules. Many authors have demonstrated that treatment with ATRA modulates
the expression of adhesive molecules in acute promyelocytic leukemia cells such as
CD11b, CD 18, CDw65, VLA-4, LFA-1 and ICAM-1 (CD54) (Di Noto
et al.
1994,
Cunha De Santis
et al
. 2007). For NB4 cells, ATRA upregulated the expression of
adhesion molecules CD11a, CD11b, CD11c, CD54, CD66c and CD138, consistent
with the increased adhesiveness of leukemia cells observed for acute promyelocytic
leukemia patients treated with ATRA (Cunha De Santis
et al
. 2007, Barber
et al
.
2008). Interestingly, the β2 integrin LFA-1 is expressed on ATRA-treated NB4 cells
in an active form and does not require activation by cytokines or chemokines, as
normally required to induce ligand-binding. All these events might explain the
increased adhesiveness of the leukemic cells at er treatment and how they can
Recently, our group demonstrated that the treatment of acute promyelocytic
leukemia primary cells with granulocyte colony-stimulating factor (G-CSF), a
cytokine that increase the commitment of hematopoietic progenitors to terminal
dif erentiation, upregulated CD11b expression and potentiated ATRA-induced
CD18 and CD11b expression on these cells (Cunha De Santis
et al
. 2007). In the same
study, arsenic trioxide upregulated ICAM-1 in NB4 cells. h e increase in CD11b,
CD18 and CD54 expression was accompanied by a higher adhesion to Matrigel.
In addition, the injection of ATRA-treated NB4 cells in Balb/c mice resulted in an
increase of the number of myeloid cells adhered to pulmonary endothelium. Both
in vitro
and
in vivo
ef ects were blocked by pre-incubation with dexamethasone,
anti-CD54 or anti-CD18. To test the role of these adhesion molecules
in vivo
,
CD54 or CD18 knockout mice and their wild-type controls were injected with
NB4 cells and treated intraperitoneally with ATRA. h ere was an increase in lung
cell migration in wild type but not in knockout animals, coni rming the results
obtained
in vitro
. h us, these results suggest that both leukocyte and endothelial
adhesion molecules are essential for dif erentiation syndrome development.
