St. Jude Children's Research Hospital

The Hospital for Sick Children

Stephan W Morris

A Thomas Look

Qin Jiang

Xiaoli Cui

Liquan Xue

Zhigui Ma

Johann K Hitzler

Compositions and methods for the diagnosis and treatment of a cancer that is resistant to at least one anaplastic lymphoma kinase (ALK) kinase inhibitor are provided herein. The present invention is based on the discovery of mutations within ALK that confer resistance to at least one ALK kinase inhibitor. Polynucleotides and polypeptides having at least one ALK inhibitor resistance mutation are provided and find use in methods and compositions useful in the diagnosis, prognosis, and/or treatment of diseases associated with aberrant ALK activity, more particularly, those that are resistant to at least one ALK kinase inhibitors. Methods and compositions are also provided for the identification of agents that can inhibit the kinase activity and/or reduce the expression level of the ALK resistance mutants.

Methods and compositions for the diagnosis and treatment of cancer resistant to anaplastic lymphoma kinase (ALK) kinase inhibitors

The invention relates to human nucleotide sequences which occur as a result of the t(1;22)(p13;q13) chromosomal translocation event which is known to occur almost invariable in young children with acute megakaryoblastic leukemia. The translocation results in the formation of fusion genes which encode fusion proteins. The invention provides the nucleotide sequences of transcripts of the fusion genes and the amino acid sequences of the fusion proteins encoded thereby. Also provided are methods for detecting the t(1, 22) translocation, for identifying agents capable of binding to the fusion protein and for identifying agents useful for treating patients with acute megakaryoblastic leukemia.

Fusion genes associated with acute megakaryoblastoc leukemias

The present invention is based on the identification and sequence determination of a novel gene, ALK, which is fused to the gene encoding nucleophosmin (NPM) in translocations present in t(2;5) lymphoma cells. Based on homologies to other proteins, the amino acid sequence of the polypeptide encoded by the ALK (Anaplastic Lymphoma Kinase) gene is a membrane-spanning protein tyrosine kinase (PTK)/receptor. Antibodies to the ALK PTK/receptor and methods utilizing such antibodies are described, as are methods of using the ALK gene to isolate ligands for the ALK PTK/receptor.

Antibodies for recognition of alk protein tyrosine/kinase receptor

Kits for detecting chromosomal rearrangements

Method of detecting a chromosomal rearrangement involving a breakpoint in the ALK or NPM gene

Human ALK protein tyrosine kinase

The present invention is based on the identification and sequence determination of fusion proteins generated by translocation which is present in t(2:5) lymphoma cells. Using either the amino acid or nucleic acid sequences of the fusion proteins disclosed herein, the present invention provides methods of detecting and treating t(2;5) lymphoma.

Nucleic acid sequences and fusion proteins present in human t(2;5)

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Memphis, TN, United States of America

Stephan W Morris