Disclosed are: (i) methods for identifying leukemia patients who (or leukemia cells that) do not exhibit an MLL-translocation, rearrangement or MLL-partial tandem duplication but who are nonetheless susceptible to treatment with DOT1L inhibitors and (ii) methods for treating leukemia patients who (or inhibiting proliferation or inducing apoptosis of leukemia cells that) do not exhibit an MLL-translocation, rearrangement or MLL-partial tandem duplication with DOT1L inhibitors. The patients identified as susceptible and the patients (or cells) treated exhibit elevated expression of a HOX cluster gene or of a HOX cluster-associated gene. Elevated expression of such genes can be measured, e.g., by quantitating the relevant RNA and comparing it to that of a healthy individual (or cell) or to a predetermined standard or it can be inferred by determining whether the patient or cell possesses a mutation that is associated with elevated HOX cluster gene or HOX cluster associated gene expression and thereby inferring that the relevant expression with be elevated.
