Annexin II and Bleeding in Acute Promyelocytic Leukemia

Menell, Jill S.; Cesarman, Gabriela; Jacovina, Andrew T.; McLaughlin, Mary Ann; Lev, Emil; Hajjar, Katherine A.

doi:10.1056/nejm199904013401303

Cited by 373 publications

(295 citation statements)

References 55 publications

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“…Prior studies have demonstrated increased expression of annexin I and͞or II in different tumor types (36)(37)(38)(39)(40). Thus, the extent to which annexin II autoantibodies may occur in tumor types other than lung cancer requires further investigation, in particular, in cancer types in which increased annexin II has been observed previously, as in the case of glioblastoma multiforme (39), pancreatic cancer (40), and acute premyelocytic leukemia (41). Interestingly, it has been shown recently that expression of annexin I is lost in esophageal squamous cell cancer (42).…”

Section: Discussionmentioning

confidence: 94%

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

Brichory

Misek

Yim

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

283

204

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The identification of circulating tumor antigens or their related autoantibodies provides a means for early cancer diagnosis as well as leads for therapy. The purpose of this study was to identify proteins that commonly induce a humoral response in lung cancer by using a proteomic approach and to investigate biological processes that may be associated with the development of autoantibodies. Aliquots of solubilized proteins from a lung adenocarcinoma cell line (A549) and from lung tumors were subjected to two-dimensional PAGE, followed by Western blot analysis in which individual sera were tested for primary antibodies. Sera from 54 newly diagnosed patients with lung cancer and 60 patients with other cancers and from 61 noncancer controls were analyzed. Sera from 60% of patients with lung adenocarcinoma and 33% of patients with squamous cell lung carcinoma but none of the noncancer controls exhibited IgG-based reactivity against proteins identified as glycosylated annexins I and͞or II. Immunohistochemical analysis showed that annexin I was expressed diffusely in neoplastic cells in lung tumor tissues, whereas annexin II was predominant at the cell surface. Interestingly, IL-6 levels were significantly higher in sera of antibody-positive lung cancer patients compared with antibody-negative patients and controls. We conclude that an immune response manifested by annexins I and II autoantibodies occurs commonly in lung cancer and is associated with high circulating levels of an inflammatory cytokine. The proteomic approach we have implemented has utility for the development of serum-based assays for cancer diagnosis as we report in this paper on the discovery of antiannexins I and͞or II in sera from patients with lung cancer.

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Section: Discussionmentioning

confidence: 94%

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

Brichory

Misek

Yim

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

283

204

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“…Indirect Immunofluorescence Microscopy-The detection of cell surface Ann-II by indirect immunofluorescence microscopy was performed as previously described (21). PC-12 cells treated with 50 ng/ml NGF for 5 days were stained with monoclonal anti-Ann-II (1.25 g/ml) or antiAnn-VI (1.25 g/ml) and counterstained with propidium iodide.…”

Section: Methodsmentioning

confidence: 99%

“…The template for a 300-bp human Ann-II tail-specific cDNA probe was prepared as previously described (21). A cDNA probe specific for human annexin I (Ann-I) was synthesized by PCR in a 100-l volume containing 200 M dNTPs, 2.5 units of Pfu polymerase (Stratagene), 50 pmol of primers, and a HUVEC -gt11 cDNA library (36) as a template.…”

Section: Methodsmentioning

confidence: 99%

“…Ann-II is a 36-kDa member of the annexin gene family, a group of ϳ20 Ca 2ϩ -and phospholipid-binding proteins that consist of a conserved carboxyl-terminal core domain and a variable amino-terminal tail domain (19). Ann-II is expressed on the surface of smooth muscle cells, glioma cells (20), endothelial cells (17,20), and acute promyelocytic leukemia cells (21). Its expression is developmentally regulated in the chicken lens (22), the rat cerebellum (23), and the murine central nervous system (24).…”

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confidence: 99%

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Neuritogenesis and the Nerve Growth Factor-induced Differentiation of PC-12 Cells Requires Annexin II-mediated Plasmin Generation

Jacovina¹,

Zhong

Khazanova

et al. 2001

Journal of Biological Chemistry

Self Cite

104

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One of the key morphological changes associated with the nerve growth factor (NGF)-induced differentiation of rat adrenal pheochromocytoma (PC-12) cells is the growth of axon-like processes called neurites. A growing body of evidence suggests that this process may be dependent upon plasmin, a serine protease generated from plasminogen (Plg) by either urokinase Plg activator (u-PA) or tissue Plg activator (t-PA). Prior work in our laboratory has identified annexin II (Ann-II) as a coreceptor for Plg and t-PA that promotes and localizes plasmin generation near the cell surface. In the present study, we report a 3-9-fold increase in Ann-II protein and message levels in NGF-treated PC-12 cells. Message stability and nuclear run-on assays suggest that this induction occurs at the level of gene transcription. Neurite outgrowth assays on and within a three-dimensional matrix demonstrate the inhibition of NGF-induced PC-12 cell differentiation by polyclonal and monoclonal antibodies directed against Ann-II as well as by the overexpression of antisense Ann-II mRNA. Neuritogenesis is also impaired by ␣ 2 -plasmin inhibitor, antibodies directed against t-PA and u-PA, and ⑀-aminocaproic acid, a lysine analog that inhibits Plg activation and the binding of Plg to Ann-II. Plasmin generation assays reveal a 2-fold increase in plasmin production on NGF-treated PC-12 cells, which can be blocked by a polyclonal antibody directed against the tail region of Ann-II. From these data, we conclude that Ann-II is transcriptionally up-regulated by NGF and that Ann-II-mediated plasmin generation may play an important role during neurite development in the differentiating PC-12 cell.

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“…Firstly, there is activation of extrinsic pathway secondary to release of tissue factor and cancer pro-coagulant from malignant cells. Secondly, there is increased annexin II receptor expression on the surface of the leukemic promyelocytes [3]. Annexin II receptor binds plasminogen and tissue plasminogen activator and increases plasmin formation by a factor of 60, thereby leading to increased WBC white blood cell, DVT deep vein thrombosis, PE pulmonary embolism, NR not recorded, MI myocardial infarction, RV right ventricle fibrinolysis.…”

Section: Discussionmentioning

confidence: 99%

Acute Promyelocytic Leukemia Presenting as Ischemic Stroke in Young

Kapoor

Pati

Gupta

et al. 2012

Indian J Hematol Blood Transfus

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Coagulopathy in acute promyelocytic leukemia (APL) is a very complex disorder and is believed to result from interplay of various factors. Usually patients present with bleeding tendencies which can be life threatening. However, a few present with thromboses. Here, we report a young male with APL who presented with ischemic stroke in young. Case ReportA 23-year-old male presented to casualty with 1 month history of fever, symptomatic anemia followed, around 15 days later, by bleeding tendencies in the form of epistaxis, hematemesis, and melena. Two days prior to presentation to the hospital, he developed slurring of speech, pooling of secretions in mouth, and facial deviation toward the left side. His prior medical history was unremarkable with no history of hypertension, diabetes, smoking or alcohol consumption. On examination he was drowsy but arousable, disoriented to time, place, and person. He had pallor with widespread petechiae. His BP was 128/86 mmHg with temperature of 38.3°C. He was uncooperative for detailed neurological assessment; however, he had evidence of facial paresis on left side with extensor plantar on the left side. Spleen was palpable 4 cm below left costal margin. On investigation, hemoglobin (Hb) was 75 gm/l, total leukocyte count (TLC) was 85 9 10 9 /l, and platelets were 45 9 10 9 /l. Peripheral smear showed more than 90% abnormal hypergranular promyelocytes (Fig. 1). Blood chemistry was essentially normal. Coagulation profile revealed deranged prothrombin time (18 s with control of 12 s) with normal activated partial thromboplastin time (APTT), thrombin time (TT), and fibrinogen levels. D-Dimer levels were raised. Urgent noncontrast CT scan of the head was carried out which showed a hypodense area suggestive of infarct in the right parietooccipital region along with cerebral edema (Fig. 2). ECG showed sinus tachycardia with T wave inversion in anterior and lateral leads. Troponin (T) was negative. On the basis of peripheral smear findings and clinical presentation, the patient was immediately started on all-trans-retinoic acid (ATRA) at a dose of 45 mg/m 2 . As he presented in Sanz high risk category with very high TLC, ATRA was followed by parenteral daunorubicin at dose of 60 mg/m 2 . Blood component support with fresh frozen plasma, platelet concentrates, and packed RBC was given along with mannitol as the cerebral decongestant. Bone marrow examination done subsequently showed replacement by abnormal hypergranular promyelocytes with strong cytochemical positivity for myeloperoxidase (MPO) and sudan black (SBB) stains compatible with diagnosis of acute promyelocytic leukemia (APL) (Fig. 2). Immunophenotyping revealed positivity for CD 13, CD 33, CD 34, anti-MPO and negativity for HLA-DR, CD 2, CD 7, CD 79a, CD 117, and CD 19 in these cells. Coexpression of CD 10 was also noted. The diagnosis of APL was confirmed by positivity for PML-RARa (promyelocytic leukemia-retinoic acid receptor alpha) fusion transcript by reverse-transcription-polymerase chain reaction (RT-PCR). Howe...

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Annexin II and Bleeding in Acute Promyelocytic Leukemia

Abstract: Abnormally high levels of expression of annexin II on APL cells increase the production of plasmin, a fibrinolytic protein. Overexpression of annexin II may be a mechanism for the hemorrhagic complications of APL.

Cited by 373 publications

References 55 publications

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

An immune response manifested by the common occurrence of annexins I and II autoantibodies and high circulating levels of IL-6 in lung cancer

Neuritogenesis and the Nerve Growth Factor-induced Differentiation of PC-12 Cells Requires Annexin II-mediated Plasmin Generation

Acute Promyelocytic Leukemia Presenting as Ischemic Stroke in Young

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