Methods and compositions for the prognosis and treatment of relapsed leukemia
The present invention is directed to methods of prognosing relapsed leukemia in a subject. These methods are based on the detection of one or more relapse-specific gene mutations in a patient sample. The present invention further relates to methods of preventing and treating relapse leukemia in a subject based on the determined prognosis of the subject.
1. A method of inhibiting thiopurine resistance in a human subject comprising:
administering, to a human subject in need of thiopurine therapy and having one or more 5′nucleotidase, cytosolic II (NT5C2) gene mutations, an agent that inhibits mutant or wildtype NT5C2 gene expression or mutant or wildtype NT5C2 encoded enzyme activity under conditions effective to inhibit thiopurine resistance in the subject, wherein said one or more NT5C2 gene mutations is selected from the group consisting of
(i) a mutation encoding a substitution at the amino acid position corresponding to R367 of SEQ ID NO: 2,
(ii) a mutation encoding a substitution at the amino acid position corresponding to R238 of SEQ ID NO: 2,
(iii) a mutation encoding substitution at the amino acid position corresponding to S408 of SEQ ID NO: 2,
(iv) a mutation encoding a substitution at the amino acid position corresponding to S445 of SEQ ID NO: 2, and
(v) a mutation encoding an amino acid residue insertion at the amino acid position corresponding to lysine 404 of SEQ ID NO:2.
2. The method of claim 1 , wherein the agent inhibits mutant NT5C2 gene expression or mutant NT5C2 encoded enzyme activity.
3. The method of claim 1 , wherein the human subject has acute lymphoblastic leukemia.
4. The method of claim 3 , further comprising
administering to the human subject one or more anti-leukemia therapies in conjunction with said agent that inhibits mutant or wildtype NT5C2 gene expression or mutant or wildtype NT5C2 encoded enzyme activity.
5. The method of claim 1 , wherein the agent comprises a ribonucleoside 5′-monophosphate analogue.
6. The method of claim 1 , wherein said one or more NT5C2 gene mutations are within a region of the encoded cN-II protein that is involved in cN-II enzyme subunit association and dissociation.
7. The method of claim 1 , wherein the one or more NT5C2 gene mutations encode an arginine to tryptophan substitution at the amino acid position corresponding to R238 of SEQ ID NO: 2.
8. The method of claim 1 , wherein the one or more NT5C2 gene mutations encode an arginine to glutamine substitution at the amino acid position corresponding to R367 of SEQ ID NO: 2.
9. The method of claim 1 , wherein the one or more NT5C2 gene mutations encode a serine to arginine substitution at the amino acid position corresponding to 5408 of SEQ ID NO: 2.
10. The method of claim 1 , wherein the one or more NT5C2 gene mutations encode a serine to phenylalanine substitution at the amino acid position corresponding to 5445 of SEQ ID NO: 2.
11. The method of claim 1 , wherein the amino acid residue insertion comprises an aspartic acid residue insertion at the position corresponding to lysine 404 of SEQ ID NO:2.
12. The method of claim 3 , wherein the human subject has B-cell acute lymphoblastic leukemia.
13. A method of treating a human subject having leukemia comprising:
administering, to the human subject having leukemia and having one or more 5′nucleotidase, cytosolic II (NT5C2) gene mutations, a non-thiopurine based anti-leukemic therapeutic, wherein said one or more NT5C2 gene mutations is selected from the group consisting of (i) a mutation encoding a substitution at the amino acid position corresponding to R367 of SEQ ID NO: 2, (ii) a mutation encoding a substitution at the amino acid position corresponding to R238 of SEQ ID NO: 2, (iii) a mutation encoding a substitution at the amino acid position corresponding to S408 of SEQ ID NO: 2, (iv) a mutation encoding a substitution at the amino acid position corresponding to 5445 of SEQ ID NO: 2, and (v) a mutation encoding an amino acid residue insertion at the position corresponding to lysine 404 of SEQ ID NO:2.
14. The method of claim 13 , wherein the non-thiopurine based anti-leukemic therapeutic is a chemotherapeutic selected from the group consisting of vincristine, asparaginase, daunorubicin, cyclophosphamide, cytarabine, etoposide, and methotrexate.
15. The method of claim 13 , wherein the non-thiopurine based anti-leukemic therapeutic is radiotherapy.
16. The method of claim 13 , wherein the non-thiopurine based anti-leukemic therapeutic is a bone-marrow transplant.
17. The method of claim 13 , wherein the subject has acute lymphoblastic leukemia.