Abstract
Acute myeloid leukemia (AML) is a heterogeneous hematopoietic malignancy characterized by the accumulation of incompletely differentiated progenitor cells (blasts) in the bone marrow and blood, and by suppression of normal hematopoiesis. It has recently become apparent that the AML genome is characterized by recurrent mutations and dysregulations in epigenetic regulators. These mutations frequently occur before the onset of full blown leukemia, at the pre-leukemic phase, and persist in residual disease that remains after therapeutic intervention, thus suggesting that targeting the AML epigenome may help to eradicate minimal residual disease and prevent relapse. Within the AML epigenome, lysine-specific demethylase 1 A (LSD1) is a histone demethylase that is found frequently overexpressed, albeit not mutated, in AML. LSD1 is a required constituent of critical transcription repressor complexes like CoREST and nucleosome remodeling and deacetylase (NuRD), and abrogation of LSD1 expression results in impaired self-renewal and proliferation, and increased differentiation and apoptosis in AML models and primary cells, particularly in AMLs with MLL- and AML1-rearrangements, or erythroid and megakaryoblastic differentiation block. On this basis, a number of LSD1 inhibitors have been developed in the past decade, and few of them are currently being tested in clinical trials for patients with AML, along with other malignancies. To date, the most promising application of this therapeutic strategy appears to be combination therapy of LSD1 inhibitors with all-trans retinoic acid (ATRA) to reactivate myeloid differentiation in cells that are not spontaneously susceptible to ATRA treatment. In this review, we provide an overview of LSD1 function in normal hematopoiesis and leukemia, and of the current clinical application of LSD1 inhibitors for the treatment of patients with AML.
Highlights
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by vast clinical and biological heterogeneity [1]
In the context of blood neoplasms, lysine-specific demethylase 1 A (LSD1) was found overexpressed in about 60% of acute myeloid leukemia cases [14, 15], where recent work has suggested that it contributes to leukemia development and propagation by imposing a myeloid maturation arrest and promoting proliferation of myeloid progenitors [16, 17]
Unlike other epigenetic regulators like the histone methyltransferase MLL1, LSD1 has not been found mutated in AML, but it is highly expressed in leukemic blasts in about 60% of AML patients as well as in other hematological malignancies [14]
Summary
Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by vast clinical and biological heterogeneity [1]. Tal ( known as Scl1) is phosphorylated at serine 172 in the LSD1-interacting domain This modification allows LSD1–Tal interaction and LSD1 binding to promoters of Tal1-target genes involved in HSCs self-renewal, repressing their transcription through the Figure 3 | The complex function of lysine-specific demethylase 1A (LSD1) in hematopoiesis. In the last decade several reversible and irreversible LSD1 inhibitors have been developed and tested in preclinical AML models, with some of them entering clinical investigation (Table 1) [15] Overall these compounds appear to exert promising antileukemic functions primarily by altering stem cell programs, inhibiting proliferation, and restoring myeloid differentiation in AML cells, with increased efficacy for leukemia subtypes carrying MLL and AML1 rearrangements, NPM1 mutations, and erythroid and megakaryoblastic differentiation block [15]. The most potent and selective LSD1 inhibitor to date is ORY-1001 (PubChem CID: 71664305), designed by Oryzon
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