Disease biomarkers and treatment methods related thereto
The present invention features a knock-in mouse comprising a mutation in an endogenous CRBN locus and methods of use thereof.
1. A method of reducing the proliferation of a cell, the method comprising: contacting the cell with (i) lenalidomide or a lenalidomide analog; and (ii) an inhibitory nucleic acid molecule that decreases the expression of casein kinase 1A1 (CSNK1A1) polypeptide.
2. The method of claim 1 , wherein the inhibitory nucleic acid molecule is a CSNK1A1-specific antisense nucleic acid molecule, shRNA, siRNA molecule, or Crispr.
3. The method of claim 1 , wherein the cell is a B cell neoplasia cell, a hematopoietic cell, a mononuclear cell, a myeloid cell, or a myeloma cell.
4. The method of claim 1 , wherein the cell is obtained from a subject having myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
5. The method of claim 1 , wherein the lenalidomide analog is thalidomide or pomalidomide.
6. A method of treating a B cell neoplasia in a subject, the method comprising:
administering to a subject having a B cell neoplasia a casein kinase inhibitor in an effective amount to inhibit CSNK1A1 expression in the neoplasia cells, thereby treating the B cell neoplasia.
7. A method of identifying an agent that treats myelodysplastic syndrome, the method comprising: contacting a cell with the agent and detecting a decrease in casein kinase 1A1 (CSNK1A1) polypeptide level in the cell compared to the level of (CSNK1A1) polypeptide in an untreated control cell, thereby identifying the agent as treating myelodysplastic syndrome.
8. A method of treating a patient having a hematopoietic or myeloid cell disease or disorder, wherein said patient is pre-selected as having a hematopoietic or myeloid cell disease or disorder which is sensitive to lenalidomide or a lenalidomide analog by:
(i) contacting a cell from the patient having a hematopoietic or myeloid cell disease or disorder with lenalidomide or a lenalidomide analog; and
(ii) assaying the cell to detect sensitivity to lenalidomide or a lenalidomide analog by detecting a decrease in the level of casein kinase 1A1 (CSNK1A1) polypeptide in the cell compared to the amount of said polypeptide in an untreated or non-disease control cell, or by detecting an increase in the level of ubiquitinated CSNK1A1 polypeptide in the cell compared to the amount of said ubiquitinated polypeptide in an untreated or non-disease control cell; and
administering an effective amount of lenalidomide or a lenalidomide analog to the pre-selected patient to treat the hematopoietic or myeloid cell disease or disorder.
9. The method of claim 8 , wherein the lenalidomide analog is thalidomide or pomalidomide.
10. The method of claim 8 , wherein the hematopoietic or myeloid cell disease or disorder is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
11. A method of treating a patient having a hematopoietic or myeloid cell disease or disorder, wherein said patient is pre-selected for having a hematopoietic or myeloid cell disease or disorder which is resistant to lenalidomide or a lenalidomide analog by:
(i) contacting a cell from the patient having a hematopoietic or myeloid cell disease or disorder with lenalidomide or a lenalidomide analog; and
(ii) assaying the cell to detect resistance to lenalidomide or a lenalidomide analog by detecting no significant decrease in the level of casein kinase 1A1 (CSNK1A1) polypeptide in the cell compared to the amount of said polypeptide in an untreated or non-disease control cell, or by detecting no significant increase in the level of ubiquitinated CSNK1A1 polypeptide in the cell compared to the amount of said ubiquitinated polypeptide in an untreated or non-disease control cell; and
administering an effective amount of a non-lenalidomide or a non-lenalidomide analog drug to the pre-selected patient to treat the hematopoietic or myeloid cell disease or disorder.
12. The method of claim 11 , wherein the lenalidomide analog is thalidomide or pomalidomide.
13. The method of claim 11 , wherein the hematopoietic or myeloid cell disease or disorder is myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).
14. The method of claim 11 , wherein the patient has myelodysplastic syndrome and is treated with azacitidine or decitabine.
15. The method of claim 6 , wherein the casein kinase 1 inhibitor is D4476.
16. The method of claim 11 , wherein the non-lenalidomide or non-lenalidomide analog drug is anti-neoplastic therapy, [(1R)-3-methyl-1-[[(2S)-3-phenyl-2-(pyrazine-2-carbonylamino)propanoyl]amino]butyl]boronic acid, or corticosteroids.