Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models

M. Bianco, Anna Gasparri, Luca Generoso, E. Assi, B. Colombo, L. Scarfo, M. T. Bertilaccio, C. Scielzo, Pamela Ranghetti, Eleonora Dondossola, M. Ponzoni, F. Caligaris-Cappio, P. Ghia, A. Corti

Research output: Contribution to journalArticle

Abstract

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.3 mug, i.v., or 1.5 mug/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Emu-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2-/-gammac-/- mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro, CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA1-373), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.
Original languageEnglish
Pages (from-to)41725-41736
Number of pages12
JournalOncotarget
Volume7
Issue number27
Publication statusPublished - 2016

Fingerprint

Chromogranin A
B-Cell Chronic Lymphocytic Leukemia
Bone Marrow
Heterografts
Dromaiidae
Lymphoid Tissue
Transgenic Mice
Cell Movement
B-Lymphocytes
Animal Models
Body Weight
Kidney
Bone and Bones
Lung
Peptides

Keywords

  • chromogranin A
  • chronic lymphocytic leukemia
  • endothelial barrier function
  • tumor cell trafficking
  • vasostatin-1

Cite this

Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models. / Bianco, M.; Gasparri, Anna; Generoso, Luca; Assi, E.; Colombo, B.; Scarfo, L.; Bertilaccio, M. T.; Scielzo, C.; Ranghetti, Pamela; Dondossola, Eleonora; Ponzoni, M.; Caligaris-Cappio, F.; Ghia, P.; Corti, A.

In: Oncotarget, Vol. 7, No. 27, 2016, p. 41725-41736.

Research output: Contribution to journalArticle

Bianco, M, Gasparri, A, Generoso, L, Assi, E, Colombo, B, Scarfo, L, Bertilaccio, MT, Scielzo, C, Ranghetti, P, Dondossola, E, Ponzoni, M, Caligaris-Cappio, F, Ghia, P & Corti, A 2016, 'Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models', Oncotarget, vol. 7, no. 27, pp. 41725-41736.
Bianco, M. ; Gasparri, Anna ; Generoso, Luca ; Assi, E. ; Colombo, B. ; Scarfo, L. ; Bertilaccio, M. T. ; Scielzo, C. ; Ranghetti, Pamela ; Dondossola, Eleonora ; Ponzoni, M. ; Caligaris-Cappio, F. ; Ghia, P. ; Corti, A. / Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models. In: Oncotarget. 2016 ; Vol. 7, No. 27. pp. 41725-41736.
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T1 - Inhibition of chronic lymphocytic leukemia progression by full-length chromogranin A and its N-terminal fragment in mouse models

AU - Bianco, M.

AU - Gasparri, Anna

AU - Generoso, Luca

AU - Assi, E.

AU - Colombo, B.

AU - Scarfo, L.

AU - Bertilaccio, M. T.

AU - Scielzo, C.

AU - Ranghetti, Pamela

AU - Dondossola, Eleonora

AU - Ponzoni, M.

AU - Caligaris-Cappio, F.

AU - Ghia, P.

AU - Corti, A.

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PY - 2016

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N2 - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.3 mug, i.v., or 1.5 mug/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Emu-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2-/-gammac-/- mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro, CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA1-373), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.

AB - Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of leukemic B cells in peripheral blood, bone marrow (BM) and lymphoid tissues, and by their recirculation between these compartments. We observed that circulating chromogranin A (CgA) and its N-terminal fragment (called vasostatin-1, CgA1-76), two neuroendocrine secretory polypeptides that enhance the endothelial barrier function, are present in variable amounts in the blood of CLL patients. Studies in animal models showed that daily administration of full-length human CgA1-439 (0.3 mug, i.v., or 1.5 mug/mouse, i.p.) can reduce the BM/blood ratio of leukemic cells in Emu-TCL1 mice, a transgenic model, and decrease BM, lung and kidney infiltration in Rag2-/-gammac-/- mice engrafted with human MEC1 CLL cells, a xenograft model. This treatment also reduced the loss of body weight and improved animal motility. In vitro, CgA enhanced the endothelial barrier integrity and the trans-endothelial migration of MEC1 cells, with a bimodal dose-response curve. Vasostatin-1, but not a larger fragment consisting of N-terminal and central regions of CgA (CgA1-373), inhibited CLL progression in the xenograft model, suggesting that the C-terminal region is crucial for CgA activity and that the N-terminal domain contains a site that is activated by proteolytic cleavage. These findings suggest that circulating full-length CgA and its fragments may contribute to regulate leukemic cell trafficking and reduce tissue infiltration in CLL.

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KW - tumor cell trafficking

KW - vasostatin-1

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EP - 41736

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

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