Genetics of APL and the molecular basis of retinoic acid treatment

Casini, Tullia; Grignani, Francesco; Pelicci, Pier Giuseppe

doi:10.1002/(sici)1097-0215(19970207)70:4<473::aid-ijc17>3.0.co;2-g

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…q 2001 Blackwell Science Ltd, British Journal of Haematology 113: 989±1000 differentiation of APL cells in vitro and in vivo in the granulocyte direction (Fenaux, 1993;Grignani et al, 1994;Casini et al, 1997). The feared and sometimes fatal complication of RA therapy is the RA syndrome (Frankel et al, 1992), which is characterized by leucocytosis, fever and pulmonary infiltrations.…”

Section: Discussionmentioning

confidence: 99%

Intercellular adhesion molecule‐1 in extravasation of normal mononuclear and leukaemia cells

Mustjoki¹,

Alitalo²,

Elonen

et al. 2001

Br J Haematol

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Summary. Interaction of intercellular adhesion molecules (ICAMs) with their receptors has a key role in normal leucocyte adhesion and migration, whereas in leukaemia this has not been well established. In this study, we have evaluated the roles of different adhesion molecules in normal and leukaemia cell extravasation in a novel organotypic model for vessel wall and measured plasma ICAM-1 and -2 levels in acute leukaemia patients at diagnosis and during chemotherapy. We found that both normal mononuclear cells and blast cells from acute leukaemia patients, as well as retinoic acid-treated promyelocytic leukaemia cells, rapidly extravasated through endothelial cell layers into the underlying collagen matrix. ICAM-1 antibody prevented the extravasation, while antibodies to other adhesion molecules showed little (CD18, ICAM-2) or no inhibition (CD11a and ICAM-3). Soluble ICAM-1 (sICAM-1) protein had no effect. We also observed increased plasma sICAM-1 and -2 levels in leukaemia patients and found that they correlated only weakly with the white blood cell count. No correlation was found between sICAM-1 or -2 levels and the response to therapy. Although elevated sICAM-2 levels decreased rapidly during chemotherapy, sICAM-1 levels did not. Because sICAM-1 protein had no effect on leukaemia cell extravasation in vitro, it is probable that the increased plasma sICAM-1 levels in leukaemia patients may not play a role in leukaemia cell infiltration. However, as we showed that ICAM-1 mediated leukaemia cell extravasation on the cell surface, it is possible that cellular ICAM-1 has an important role in disease progression.

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Section: Discussionmentioning

confidence: 99%

Intercellular adhesion molecule‐1 in extravasation of normal mononuclear and leukaemia cells

Mustjoki¹,

Alitalo²,

Elonen

et al. 2001

Br J Haematol

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“…The resulting PMLIRAR-a fusion protein has been shown to have a leukemogenic role in APL. Patients with APL are treated with all-trans-retinoic acid (ATRA), which induces differentiation of APL cells in vitro and in vivo (2,5). It also reduces the bleeding tendency, which is often associated with APL (6).…”

Section: Classification a N D Clinical Findings In Leukemiamentioning

confidence: 99%

Plasminogen activation in human leukemia and in normal hematopoietic cells

Mustjoki

Alitalo

Stephens

et al. 1999

APMIS

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The active process of pericellular proteolysis is central in tumor invasion, and in particular the essential role of the urokinase‐type plasminogen activator (uPA) is well established. uPA‐mediated plasminogen activation facilitates cell migration and invasion through extracellular matrices by dissolving connective tissue components. uPA, its receptor (uPAR) and plasminogen activator inhibitor‐1 (PAI‐1) are enriched in several types of tumors. The importance of proteolysis and especially plasminogen activation is less clear in hematopoietic malignancies than in solid tumors. However, patients with leukemia have an increased tendency to bleeding, not always attributable to thrombocytopenia, and tissue infiltration by leukemic cells, processes in which plasminogen activation may be involved. Several studies have indicated that plasminogen activators (PAs) are highly expressed by cultured leukemia cells. Furthermore, differing from adherent tumor cells, leukemic cells have an enhanced capacity to activate pro‐uPA and mainly the active form of uPA is released to culture medium. Ex vivo studies have shown that uPAR, uPA and its inhibitors can be found on the surface of normal blood cells and on the blast cell surfaces from patients with acute leukemia as well as from plasma samples. Elevated levels of PAs and their inhibitors have been detected in leukemic cell lysates. Few studies have tried to demonstrate a correlation between prognosis of leukemia and levels of plasminogen activators. More in vivo studies are needed to show, if any of the factors of the plasminogen activation process can be used as tools in subclassification or as markers for prognosis in leukemia. This review article will focus on the in vivo studies of plasminogen activation in leukemia and will present several in vitro findings on PAs in normal leukocytes and leukemic cell lines.

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“…[11][12][13] At cellular level, in the nucleus, PML/RAR␣ displaces PML from nuclear bodies structures (NBs) to illdefined microspeckled nuclear structures and since PML has growth suppressive properties, such loss of specific PML localization could antagonize its function. [14][15][16][17] Remarkably, cell maturation of APL cells can be restored, to some extent, by retinoic acid treatment 18,19 and a single course of RA is sufficient to cause clinical remission in APL patients. 20 RA treatment induces a progressive disappearance of the PML/RAR␣ microspeckles and restores the normal localization of PML on PML-NBs.…”

Section: Introductionmentioning

confidence: 99%

In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RARα protein and the PML retargeting on PML-nuclear bodies

Giannı̀

Thé

1999

Leukemia

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CD437-induced apoptosis has been investigated in NB4, a human t(15;17) acute promyelocytic leukemia (APL) cell line, and in the retinoic acid (RA)-resistant NB4-R1 derivative subclone. Both NB4 and NB4-R1 cells underwent rapid apoptosis in response to low doses of CD437 (10 −7 M). This apoptosis did not require the activation of classical retinoid receptors and like arsenic (As)-induced apoptosis was preceded by the rapid activation of a caspase-3-like enzymatic activity as indicated by the increase of DEVD-pNA hydrolytic activity, by the processing of procaspase-3 protein and by the cleavage of poly(ADP-ribose) polymerase (PARP). Furthermore, it was demonstrated that the caspase-3-like proteolytic activity is responsible for the degradation of both the PML/RAR␣ oncogenic protein and the normal RAR␣ proteins. In CD437-treated cells, PML proteins were not degraded and PML relocalization on PMLNBs occurred in all the cells before death. CD437-induced apoptosis and receptor degradation were proteasome independent and not influenced either by inhibitors of protein tyrosine kinases (PTK), protein tyrosine phosphatases (PTPases) and serine proteases or by glutathione levels. Moreover, our data suggested that as for As 2 O 3 -induced apoptosis Bc12 modulation is not significant for CD437-induced apoptosis of NB4 cells. Since CD437 induces in vitro the rapid apoptosis of both RA-sensitive and -resistant APL cells, it could represent the first retinoid potentially able to eradicate in vivo malignant leukemia blasts.

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Genetics of APL and the molecular basis of retinoic acid treatment

Cited by 8 publications

References 17 publications

Intercellular adhesion molecule‐1 in extravasation of normal mononuclear and leukaemia cells

Intercellular adhesion molecule‐1 in extravasation of normal mononuclear and leukaemia cells

Plasminogen activation in human leukemia and in normal hematopoietic cells

In acute promyelocytic leukemia NB4 cells, the synthetic retinoid CD437 induces contemporaneously apoptosis, a caspase-3-mediated degradation of PML/RARα protein and the PML retargeting on PML-nuclear bodies

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