Targeting chromatin regulators inhibits leukemogenic gene expression in npm1 mutant leukemia
AssigneeMemorial Sloan Kettering Cancer Center
InventorScott A. ARMSTRONG
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Abstract
Disclosed are methods for inhibiting proliferation of or inducing apoptosis in certain leukemia cells or both. The methods comprise contacting a leukemia cell exhibiting an NPM1 mutation with a pharmacologic inhibitor of interaction between MLL and menin. More broadly, disclosed are methods for treating a susceptible leukemia using pharmacologic inhibition of Menin-MLL interaction. Also disclosed are methods for treating such leukemias using inhibition of Menin-MLL interaction in combination with DOT1L inhibition.
Claims24
A method for inhibiting proliferation of or inducing apoptosis in a leukemia cell, or for both inhibiting proliferation and inducing apoptosis in the cell, said method comprising contacting said leukemia cell with an inhibitor of interaction between MLL and menin, wherein said leukemia cell exhibits an NPM1 mutation.
A method for treating a patient afflicted with a leukemia, comprising:
- administering to said patient an inhibitor of interaction between MLL and menin, in an amount effective to inhibit proliferation and/or enhance apoptosis of leukemic cells of the patient;
- said patient being afflicted with a leukemia that exhibits an NPM1 mutation.
A method for treating leukemia in a patient previously identified as afflicted by a leukemia exhibiting an NPM1 mutation, the method comprising:
- administering to said patient an inhibitor of interaction between MLL and menin in an amount effective to inhibit proliferation and/or enhance apoptosis of leukemic cells of the patient.
A method for determining susceptibility of a leukemia patient to treatment with an inhibitor of interaction between MLL and menin alone or in combination with a DOT1L inhibitor, said method comprising:
- testing a leukemia tissue sample or cell obtained from the patient for the presence of an NMP1 mutation;
- and
- (i) selecting the patient as a candidate for treatment with an inhibitor of interaction of MLL with menin alone or in combination with a DOT1L inhibitor if the sample tests positive for said mutation;
- or
- (ii) eliminating the patient as a candidate for said treatment if the sample tests negative for said mutation.
A method for predicting the therapeutic efficacy of an inhibitor of interaction between MLL and menin alone or in combination with a DOT1L inhibitor in a leukemia patient wherein the patient does not exhibit an MLL-translocation, an MLL-rearrangement, and/or an MLL-partial tandem duplication, said method comprising:
- testing a leukemia tissue sample or cell from said patient for the presence of an NPM1 mutation,
- wherein the presence of said mutation in said sample or cell is predictive of the therapeutic efficacy of the inhibitor of MLL-menin interaction alone or in combination with a DOT1L inhibitor in the patient.
A method for inhibiting the proliferation and/or inducing apoptosis of a leukemia cell, said method comprising
- contacting said leukemia cell with an inhibitor of interaction between MLL and menin, alone or in combination with a DOT1L inhibitor,
- wherein said leukemia cell exhibits an NPM1 mutation and wherein said cell does not exhibit a genetic mutation, alteration, and/or abnormality that is an MLL-translocation (MLL-t), an MLL-rearrangement (MLL-r), or an MLL-partial tandem duplication (MLL-PTD).
A method for treating a leukemia patient wherein an NPM1 mutation has been identified in a tissue sample or cell of the patient, said method comprising:
- administering to said patient one or more inhibitors of interaction between MLL and menin alone or in combination with a DOT1L inhibitor, in amounts individually or combinedly effective in the treatment of leukemia;
- wherein the patient does not also exhibit a genetic mutation, alteration, and/or abnormality is selected from the group consisting of an MLL-t, an MLL-r, and/or an MLL-PTD.
Dependencies are inferred from the claim text.