Lysine-Specific Demethylase 1A as a Promising Target in Acute Myeloid Leukemia

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.

LSD1/KDM1A, a Gate-Keeper of Cancer Stemness and a Promising Therapeutic Target

“…The TLX-LSD1/RCOR2 axis is functional both in NSPCs and GSCs, where it positively regulates stemness gene expression (Sox2, Oct4). Finally, the frequently promoting effect of LSD1 inhibition on the differentiation of normal SCs is increasingly used as a therapeutic approach in the most undifferentiated and aggressive human malignancies (AML, glioblastoma, or HCC) [121,131,132] with promising preclinical outcomes, validating their entry into clinical trials (Tables 1 and 2).…”

“…However, it should be pointed out that these clinical studies do not include functional assays that can assess this parameter yet. Similarly, in most of the pre-clinical studies on LSD1 inhibition [83,131,132] the outcome is usually evaluated through its bulk characteristics i.e., tumor growth/volume, survival, dosing, and toxicity, leaving the effect on the CSC content elusive, with a few exceptions [105,106]. In our opinion, the solid findings provided by the basic research reports we presented herein prove that the regulation of CSCs by LSD1 is an important aspect of its role in cancer and it should be evaluated in all preclinical and clinical future studies.…”

Jmjd1c is dispensable for healthy adult hematopoiesis and Jak2V617F-driven myeloproliferative disease initiation in mice

“…The emergence of histone demethylases as novel targets in the treatment of myeloid malignancies is highlighted by the fact that several LSD1 inhibitors are already under clinical investigation [9] and JMJC domain-containing demethylase inhibiting substances are in development. While our previous results indicate a possible role for JMJD1C in the pathophysiology of MPN (1), its function in these disorders has not been investigated.…”

Lysine-Specific Demethylase 1 (LSD1/KDM1A) Is a Novel Target Gene of c-Myc

“…In AML, glioblastoma and prostate cancer, overexpression of c-Myc or LSD1 has already been reported. 32, [38][39][40][41] However, there is no report on whether both are overexpressed together. Therefore, we examined the relationship between LSD1 expression and c-Myc expression in various human tumors [31][32][33][34] in The Cancer Genome Atlas (TCG A) database using cBioPortal.…”