BCR-ABL TRUNCATION MUTATIONS

• US 20110072889A1
• Filed: 09/28/2010
• Published: 03/31/2011
• Est. Priority Date: 09/30/2009
• Status: Active Grant

• Current Assignee: Quest Diagnostics Investments Incorporated (Quest Diagnostics Incorporated)
• Original Assignee: Quest Diagnostics Investments Incorporated (Quest Diagnostics Incorporated)
• Inventors: Ma, Wanlong, Albitar, Maher
• Granted Patent: US 9,488,656 B2
• Time in Patent Office: Days
• US Class Current: 73/53.01
• CPC Class Codes: C12Q 1/6816 characterised by the detection means C12Q1/6804 takes precedence
• CPC Class Codes: C12Q 1/686 Polymerase chain reaction [PCR]
• CPC Class Codes: C12Q 1/6883 for diseases caused by alterations of genetic material
• CPC Class Codes: C12Q 2600/106 Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
• CPC Class Codes: C12Q 2600/118 Prognosis of disease development
• CPC Class Codes: C12Q 2600/156 Polymorphic or mutational markers
• CPC Class Codes: C12Q 2600/158 Expression markers
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 2800/54 Determining the risk of relapse
• CPC Class Codes: G01N 33/5748 involving oncogenic proteins

Abstract

Truncation variants of BCR-ABL mRNA that produces BCR-ABL proteins with a truncated C-terminus and its role in resistance to treatment with kinase inhibitors is described. Vectors for expressing the truncated gene products are described as well as recombinant cells that express the truncated gene products from cDNA constructs. Also provided are methods compositions and kits for detecting the BCR-ABL truncation variants. Also provided are methods for determining the prognosis of a patient diagnosed as having myeloproliferative disease, and methods for predicting the likelihood for resistance to a treatment with tyrosine kinase inhibitor in a patient diagnosed as having myeloproliferative disease. Additionally, methods for screening BCR-ABL tyrosine kinase domain inhibitors which rely on the recombinant cells are also disclosed.

Claims

1. A method for determining the prognosis of a patient diagnosed as having a myeloproliferative disease comprising:

a) assessing the BCR-ABL nucleic acid of said patient for the presence or absence of one or more BCR-ABL truncation mutations selected from the group consisting of Del 2595-2779, 2417insCAGG, Del 2596-2597, and C2506T, and

b) identifying said patient as having poor prognosis when said one or more mutations are present in BCR-ABL nucleic acid relative to an individual without said one or more mutations in BCR-ABL nucleic acid.

2. The method of claim 1, wherein said myeloproliferative disease is CML.

3. The method of claim 1, wherein said myeloproliferative disease is ALL.

4. A method for predicting the likelihood for resistance to treatment with a tyrosine kinase inhibitor in a patient diagnosed as having a myeloproliferative disease, comprising:

(a) assessing the BCR-ABL nucleic acid obtained from the patient for the presence or absence of one or more BCR-ABL mutations selected from the group consisting of Del 2595-2779, Del 2596-2597, 2417insCAGG, and C2506T; and

(b) identifying said patient as having a likelihood of resistance to a tyrosine kinase inhibitor when one or more said mutations are present.

5. The method of claim 4, wherein said tyrosine kinase inhibitor is one or more selected from the group consisting of imatinib, nilotinib and dasatinib.

6. The method of claim 4, wherein said tyrosine kinase inhibitor is imatinib.

7. The method of claim 4, wherein said myeloproliferative disease is CML.

8. The method of claim 4, wherein said myeloproliferative disease is ALL.

9. The method of claim 4, wherein said patient is being administered a tyrosine kinase inhibitor.

10. The method of claim 9, wherein said tyrosine kinase inhibitor is one or more selected from the group consisting of imatinib, nilotinib and dasatinib.

11. The method of claim 10, wherein the treatment regimen of the patient is modified when at least one of said mutations is identified.

12. A method for determining the prognosis of a patient diagnosed as having a myeloproliferative disease comprising:

a) assessing a sample from said patient for the presence or absence of one or more BCR-ABL truncation mutant proteins encoded by BCR-ABL nucleic acid comprising one or more mutations, wherein said one or more mutations is selected from the group consisting of Del 2595-2779, 2417insCAGG, Del 2596-2597, and C2506T,

b) identifying said patient as having poor prognosis when said one or more BCR-ABL truncation mutant proteins are present in said patients sample relative to an individual without said one or more BCR-ABL truncation mutant proteins.

13. The method of claim 12, wherein said myeloproliferative disease is CML.

14. The method of claim 12, wherein said myeloproliferative disease is ALL.

15. A method for predicting the likelihood for resistance to treatment with a tyrosine kinase inhibitor in a patient diagnosed as having a myeloproliferative disease, comprising:

(a) assessing the BCR-ABL protein obtained from the patient for the presence or absence of one or more BCR-ABL truncations encoded by BCR-ABL mutations selected from the group consisting of Del 2595-2779, Del 2596-2597, 2417insCAGG, and C2506T; and

(b) identifying said patient as having a likelihood of resistance to a tyrosine kinase inhibitor when one or more said mutations are present.

16. The method of claim 15, wherein said tyrosine kinase inhibitor is one or more selected from the group consisting of imatinib, nilotinib and dasatinib.

17. The method of claim 15, wherein said tyrosine kinase inhibitor is imatinib.

18. The method of claim 15, wherein said myeloproliferative disease is CML.

19. The method of claim 15, wherein said myeloproliferative disease is ALL.

20. The method of claim 15, wherein said patient is being administered a tyrosine kinase inhibitor.

21. The method of claim 20, wherein said tyrosine kinase inhibitor is one or more selected from the group consisting of imatinib, nilotinib and dasatinib.

22. The method of claim 20, wherein the treatment regimen of the patient is modified when at least one of said mutations is identified.