Although epigenetic mechanisms are implicated in the pathoge

Although epigenetic mechanisms are implicated in the pathogenesis of hematopoietic malignancies, little is known about the role of lysine-specific histone demethylases and whether manipulation of these enzymes can be translated into targeted therapies. KDM6A is the most frequently mutated histone demethylase in hematopoietic malignancies and in a broad spectrum of solid tumors 25, 26. Loss-of-function mutations or deletion of KDM6A is prominent in NOTCH1-driven T-cell acute lymphoblastic leukemia (T-ALL), and these mutations predominantly occur in male patients [26]. In the context of NOTCH1, leukemia kinetics were consistently faster in Kdm6a mice with shorter latency compared with wild-type animals [25]. Gene expression and chromatin immunoprecipitation sequencing (ChIP-seq) studies showed that KDM6A positively controls tumor suppressor genes including the regulator of NOTCH1 stability, FBXW7, and counteracts the activity of PRC2. The latter rendered T-ALL driven by KDM6A inactivation sensitive to pharmacologic inhibition of H3K27 methylation [26]. Intriguingly, a pro-oncogenic role for KDM6A has been reported recently in TAL1-positive leukemias [27], suggesting that the impact of KDM6A inactivation in T-ALL is context dependent. Furthermore, KDM6B, the other known H3K27 demethylase, was found to be essential for the initiation and maintenance of T-ALL [25]. KDM6B is induced by the NF-kB pathway and regulates the NOTCH1 targets HES1 and HEY1. Treatment of T-ALL cell lines with the KDM6B small-molecule inhibitor GSKJ4 led to Methyllycaconitine citrate sale arrest and increased apoptosis. Overall, these findings provide a basis for the development of personalized epigenetic therapies for T-ALL with respect to the status of KDM6A and KDM6B and highlight the context-dependent role of these enzymes in T-cell transformation 25, 26, 27. Another example of a histone demethylase with a context-dependent role in hematopoietic transformation is KDM2B, originally cloned as a putative oncogene from an insertional mutagenesis screen in Moloney murine leukemia virus-induced T-cell lymphomas 28, 29. KDM2B is an integral component of a noncanonical PRC1 complex and cooperates with PRC2 to regulate senescence, differentiation, and oncogenesis 17, 28, 30, 31, 32, 33. KDM2B is upregulated in and required for the oncogenicity of human ALL cell lines, whereas its overexpression in Sca-1+ cells suffices to induce mixed-lineage leukemias with complete penetrance in mice 17, 34. Conversely, deletion of KDM2B expands myeloid progenitors and accelerates Kras-driven acute myeloid leukemia (AML) through subversion of lineage specification pathways [17]. Although KDM2B is neither mutated nor exhibits copy number changes in leukemia, its expression is downregulated in AML; similarly, its interacting partners, including BCOR and components of PRC2, are frequently inactivated and confer poor prognosis 17, 35, 36. Therefore, modulation of KDM2B activity may be directed to restore differentiation in acute leukemias and to improve the efficacy of current therapies. Overexpression of KDM1A is observed frequently in leukemia and confers a poor prognosis by blocking differentiation and maintaining a “stem-like” phenotype of leukemia-initiating cells (LICs) 37, 38. Overexpression of the shortest isoform of Kdm1a, which demethylates histone H3K9 preferentially and is repressed in quiescent HSCs, sufficed to induce T-ALL/lymphoma in mice [39]. Inhibition of the enzyme with small-molecule inhibitors as well as knock-down of the endogenous protein resulted in increased apoptosis and impaired leukemogenicity of MLL-AF9-driven AML [37]. Similar results were obtained in acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of AML characterized by the t(15;17)-associated PML-RARA fusion, in which all-trans-retinoic acid (ATRA) is used to differentiate leukemic blasts. The combination of KDM1A inhibition and ATRA administration had a synergistic therapeutic effect, even in non-APL AML [38]. In that context, ChIP-seq studies revealed that ablation of KDM1A increased H3K4me2 and expression of myeloid lineage–specific genes, suggesting that differentiation of leukemic blasts with “epi-drugs” holds promise for the treatment of AML [38].