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Inside this Issue: March/April

Posted By Connections Editor, Thursday, April 14, 2016
Updated: Monday, April 11, 2016


Combination epigenetic and immunotherapy overcomes resistance to monoclonal antibodies in hematologic malignancies: A new therapeutic approach
Elliot M. Epner, Bikramajit Singh Saroya, Zainul S. Hasanali, Thomas P. Loughran  

  • Cladribine, histone deacetylase inhibitor, and alemtuzumab constitute an effective therapy for T-cell prolymphocytic leukemia.
  • Cladribine and histone deacetylase inhibitor induce CD30 and allow for brentuximab vedotin therapy in T-cell prolymphocytic leukemia.
  • The combination of DNA methyltransferase inhibitor, histone deacetylase inhibitor, and monoclonal antibody therapy is an effective treatment paradigm for cancer.
  • Antibody-dependent cell-mediated cytotoxicity is central to the mechanism of action of monoclonal antibody therapy.

CD44 promotes chemoresistance in T-ALL by increased drug efflux
Catherine Hoofd, Xuehai Wang, Sonya Lam, Catherine Jenkins, Brent Wood, Vincenzo Giambra, Andrew P. Weng 

  • Chemotherapy selected for increased CD44 expression in a mouse model of T-cell acute lymphoblastic leukemia (T-ALL).
  • Enforced CD44 expression in mouse and human T-ALL cells enhanced chemoresistance.
  • CD44 knockdown or treatment with blocking antibody enhanced chemosensitivity.
  • CD44 enhanced drug efflux activity in human T-ALL cells.
  • Patients undergoing induction chemotherapy had elevated CD44 levels in residual blasts.

Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia
Wen Tian Sun, Wei Xiang, Bee Ling Ng, Kartini Asari, Ralph M. Bunte, Patrick J. Casey, Mei Wang, Charles Chuah 

  • Isoprenylcysteine carboxylmethyltransferase inhibition enhances the effect of BCR-ABL tyrosine kinase inhibition.
  • Cysmethynil, an isoprenylcysteine carboxylmethyltransferase inhibitor, augments tyrosine kinase inhibitor-induced apoptosis in chronic myeloid leukemia cells.
  • The combination of cysmethynil and imatinib inhibits colony formation in primary chronic myeloid leukemia cells.
  • The in vivo effects of the cysmethynil/imatinib combination are enhanced compared with the effects of either drug alone.
  • Enhanced apoptosis may be caused by immediate and persistent inhibition of MAPK signaling.

Fms-like tyrosine kinase 3 (Flt3) ligand depletes erythroid island macrophages and blocks medullar erythropoiesis in the mouse
Rebecca N. Jacobsen, Bianca Nowlan, Marion E. Brunck, Valerie Barbier, Ingrid G. Winkler, Jean-Pierre Levesque

  • Daily administration of Flt3 ligand in mice depletes erythroblastic island macrophages and inhibits erythropoiesis in the bone marrow.
  • Suppression of medullary erythropoiesis is compensated by increases in erythroblastic island macrophage numbers and erythropoiesis in the spleen.
  • The suppressive effect of Flt3 ligand on medullary erythroblastic island macrophages and erythropoiesis is likely to be indirect, as
  • Flt3 receptor is not expressed by macrophages or erythroid progenitors.



Ex vivo evaluation of the effect of regulatory T cells on the anti-tumor activity of bortezomib in multiple myeloma
Ayse Pinar Ercetin, Mehmet Ali Ozcan, Safiye Aktas, Faize Yuksel, Serife Medeni Solmaz, Gokmen Omur Sevindik, Abdullah Katgi, Ozden Piskin, Bulent Undar

  • A primary multiple myeloma cell culture and a co-culture with host Treg cells were established.
  • The interaction between Treg cell expansion and the anti-tumor effect of bortezomib was revealed.
  • Treg cells had varied effects on bortezomib, increasing, decreasing, or not changing its anti-tumor effect on multiple myeloma.
  • Treg cells increased the ex vivo anti-tumor effect of bortezomib in patients who did not develop bortezomib resistance in vivo.
  • Treg cells decreased the ex vivo anti-tumor effect of bortezomib in patients who developed bortezomib resistance in vivo. 

Expression of the MOZ-TIF2 oncoprotein in mice represses senescence
Anne Largeot, Flor Maria Perez-Campo, Elli Marinopoulou, Michael Lie-a-Ling, Valerie Kouskoff, Georges Lacaud

  • MOZ-TIF2 transformation is associated with inhibition of senescence through repression of the CDKN2A locus.
  • MOZ histone acetyltransferase activity of MOZ-TIF2 is required for the inhibition of senescence.
  • MOZ-TIF2 acts on the p53 apoptosis-versus-senescence balance.

Erythroblast enucleation is a dynein-dependent process
Isuzu Kobayashi, Kumi Ubukawa, Kotomi Sugawara, Ken Asanuma, Yong-Mei Guo, Junsuke Yamashita, Naoto Takahashi, Kenichi Sawada, Wataru Nunomura

  • Dynein was expressed during terminal differentiation of human erythroblasts.
  • Inhibition of dynein blocked the cell proliferation of colony-forming units–erythroid and enucleation.
  • Dynein was distributed in aggregates on the periphery of the nucleus in erythroblasts.
  • Cell polarization was blocked in the dynein inhibitor-treated erythroblasts.
  • Enucleation of human erythroblasts requires cell polarization by dynein.

Mobilization of hematopoietic stem cells with highest self-renewal by G-CSF precedes clonogenic cell mobilization peak
Ingrid G. Winkler, Eliza Wiercinska, Valerie Barbier, Bianca Nowlan, Halvard Bonig, Jean-Pierre Levesque 

  • After 2 days of administration of granulocyte colony-stimulating factor, mouse blood contains high levels of serially reconstituting hematopoietic stem cells.
  • In mice, mobilization of serially reconstituting hematopoietic stem cells precedes that of clonogenic progenitors.
  • In half of healthy volunteers tested, after 2 days of administration of granulocyte colony-stimulating factor, mobilized CD34+ cells are enriched in CD34+CD38− primitive progenitors.


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