University of Pennsylvania

Temple University

Johns Hopkins University

The Children's Hospital of Philadelphia

Alan M Gewirtz

Bruno Calabretta

Curt I Civin

Mortimer Poncz

Donald Small

John Kim Choi

This invention provides methods of inducing apoptosis in a bcl--expressing cell and methods of treating a subject with a cancer comprising a bcl--expressing cell, comprising administration of a composition that reduces the amount of the bcl-6 protein or of an mRNA molecule encoding same, a composition comprising a nucleic acid molecule complementary to or corresponding to a region of the mRNA molecule, or a vector expressing the nucleic acid molecule. In another embodiment, the present invention provides an isolated nucleic acid molecule having a sequence corresponding to or complementary to accessible regions of bcl-6 mRNA, and vectors, cells, compositions, and kits comprising same.

Methods of use of bcl-6-derived nucleotides to induce apoptosis

A hybrid viral vector for transfer of selected genes to cells and mammals is provided. The vector is a hybrid of human immunodeficiency-based lentivirus and murine stem cell retrovirus.

HIV-MSCV hybrid viral vector for gene transfer

Oligonucleotides are provided having a nucleotide sequence complementary to at least a portion of the mRNA transcript of the human c-kit gene. These 'antisense' oligonucleotides are hybridizable to the c-kit mRNA transcript. Such oligonucleotides are useful in selectively inhibiting proliferation of erythroid cells, particularly in disorders characterized by an elevated hematocrit due to over-production of erythrocytes. The antisense oligomers also have activity agent hematologic neoplastic cells and are therefore suitable as bone marrow purging agents.

Antisense of oligonucleotides to c-kit proto-oncogene and in vitro

Leukemias characterized by the presence of the Philadelphia chromosome and the expression of the hybrid bcr-abl gene are treated with antisense oligonucleotides complementary to a target sequence of the bcr-abl mRNA transcript including the breakpoint junction. Individual chronic myelogoneous leukemia patients or Philadelphia chromosome-positive acute lymphocytic leukemia patients are treated by first sequencing the individual's bcr-abl breakpoint junction, and then administering antisense oligonucleotides complementary thereto. The oligonucleotides are designed to hybridize specifically to the bcr-abl breakpoint junction without substantial cross hybridization to untranslocated c-abl sequences. Treatment may comprise in vivo administration of antisense oligonucleotides, or ex vivo treatment such as bone marrow purging.

Selective inhibition of leukemic cell proliferation by bcr-abl antisense

Oligonucleotides are provided having a nucleotide sequence complementary to at least a portion of the mRNA transcript of the STK-1 gene. These 'antisense' oligonucleotides are hybridizable to the STK-1 mRNA transcript. Such oligonucleotides are useful in treating neoplastic diseases characterized by activation of STK-1 gene expression. The oligonucleotides are also useful as bone marrow purging agents in the treatment of leukemia and metastasized neoplasms.

Antisense oligonucleotides specific for STK-1 and method for inhibiting

Antisense oligonucleotides specific for the vav proto-oncogene inhibit the proliferation of malignant, but not normal, myeloid cells. The oligonucleotides are therefore useful in the treatment of leukemias, in particular, as bone marrow purging agents. The vav antisense oligonucleotides also selectively inhibit the formation of erythroid cell colonies without effect on megakaryocyte and granulocyte/macrophage colony formation. The oligonucleotides are therefore useful in treating disorders characterized by an elevated hematocrit due to overproduction of erythrocytes.

Selective inhibition of cell proliferation by vav antisense

Neutrophil activating peptide-2 or analog thereof is administered to a mammal to achieve therapeutic reduction of the number of circulating platelets. The peptide is useful in treating essential thrombocythemia and reactive thrombocytosis.

Suppression of megakaryocytopoiesis by neutrophil activating peptide-2

The effectiveness of selected antineoplastic agents may be determined in individual patients by comparing the level of expression of one or more selected growth-regulated genes in neoplastic cells taken from the patient before and shortly after the initiation of therapy. A decrement in expression is prognostic of eventual remission, while a lack of decrement indicates that remission is unlikely. The test may also be accomplished by comparing the level of expression of growth-regulated genes in neoplastic cells in culture before and after incubation of the cells with the selected antineoplastic agents.

Method for predicting the effectiveness of antineoplastic therapy in

Macrophage inflammatory protein-1 or -2, or analog thereof, is administered to a mammal to achieve therapeutic reduction of the number of circulating platelets. The proteins are useful in treating essential thrombocythemia and reactive thrombocytosis.

Suppression of megakaryocytopoiesis by macrophage inflammatory proteins

Antimaturation factor (platelet factor 4 or active peptide segments thereof) is employed in the clinical treatment of coagulation disorders as an anticoagulant operating via an autoregulator mechanism for selectively suppressing megakaryocytopoiesis. Exposure of immature megakaryocytes to antimaturation factor reversibly inhibits cell maturation and, accordingly, functions characteristic of the mature cell, including platelet production and expression of genes coding for platelet coagulation factors, are reversibly suppressed.

Suppression of megakaryocytopoiesis employing platelet factor 4

Oligonucleotides are provided having a nucleotide sequence complementary to at least a portion of the mRNA transcript of the human c-myb gene. These 'antisense' oligonucleotides are hybridizable to the c-myb mRNA transcript. Such oligonucleotides are useful in treating hematologic neoplasms and in inducing immunosuppression. They are particularly useful as bone marrow purging agents.

Growing community of inventors

Philadelphia, PA, United States of America

Alan M Gewirtz