The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

Harris, William J.; Huang, Xu; Lynch, James T.; Hitchin, James R.; Li, Yaoyong; Ciceri, Filippo; Blaser, Julian G.; Greystoke, Brigit; Jordan, Allan M.; Ogilvie, Donald; Somervaille, Tim C. P.

doi:10.1016/j.ccr.2012.05.035

Cited by 135 publications

(216 citation statements)

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“…This notion is further supported by the repressed in vitro erythroid colony formation induced by the potent TCP analogs. 18 However, in contrast to our findings granulomonocytic colony formation was reported to be unaltered by TCP analog exposure. Perhaps a monocytic lineage bias of granulomonocytic colonies was overseen because morphological or immunophenotypic colony analyses on the cellular level were not performed.…”

Section: Discussioncontrasting

confidence: 99%

“…Inhibition of LSD1 enzymatic activity by the novel TCP analogs was up to 160-fold greater than the inhibition by TCP. In line with these pharmacologic data, Harris et al 18 noted that leukemic mice treated with the novel TCP analogs were anemic and thrombocytopenic whereas Schenk et al 17 treating human AML xenografted mice with TCP did not report the occurrence of hematologic side effects. We observed anemia and thrombocytopenia in our LSD1-kd model.…”

Section: Discussionmentioning

confidence: 93%

“…This is particularly relevant, because previous studies established LSD1 as a potential drug target for cancer treatment. [13][14][15][16][17][18]42 Continuous dox treatment of shLSD1 mice resulted in dramatic changes within different hematopoietic compartments. Mechanistically, enhanced expression of hematopoietic regulatory genes in these mice is presumably caused by the lack of LSD1 repressive activity at H3K4 residues in the gene promoters.…”

Section: Discussionmentioning

confidence: 99%

“…17,18 Schenk et al 17 used the approved antidepressant drug tranylcypromin (TCP) while Harris et al 18 used recently developed, more potent and more LSD1-specific TCP analogs. Inhibition of LSD1 enzymatic activity by the novel TCP analogs was up to 160-fold greater than the inhibition by TCP.…”

Section: Discussionmentioning

confidence: 99%

“…6,[14][15][16] Strikingly, two recent studies report a central role of LSD1 in acute myeloid leukemia (AML). 17,18 These data identify LSD1 as a promising target for anticancer therapy. A prerequisite to further develop a LSD1-inhibitory therapy is to determine potential side effects.…”

Section: Introductionmentioning

confidence: 93%

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

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Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Sprüssel¹,

Schulte²,

et al. 2012

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Modulators of histone demethylase JMJD1C selectively target leukemic stem cells

Yang

Zhang

et al. 2020

FEBS Open Bio

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JMJD1C is required for the maintenance of both leukemia cells and leukemic stem cells, serving as a potential therapeutic target of acute myeloid leukemia. JDM‐7 (jumonji domain modulator #7) and a structurally similar compound, tadalafil, a drug approved by the US Food and Drug Administration, are able to bind to JMJD1C, resulting in strong attenuation of leukemic stem cells and mild attenuation of leukemia cells, thereby repressing acute myeloid leukemia.

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Clinical activity of CC‐90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies

Hollebecque

Salvagni

Plummer

et al. 2022

Cancer

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Background CC‐90011 is an oral, potent, selective, reversible inhibitor of lysine‐specific demethylase 1 (LSD1) that was well tolerated, with encouraging activity in patients who had advanced solid tumors or relapsed/refractory marginal zone lymphoma. The authors present long‐term safety and efficacy and novel pharmacodynamic and pharmacokinetic data from the first‐in‐human study of CC‐90011. Methods CC‐90011‐ST‐001 (http://clincaltrials.gov identifier NCT02875223; Eudract number 2015–005243‐13) is a phase 1, multicenter study in which patients received CC‐90011 once per week in 28‐day cycles. The objectives were to determine the safety, maximum tolerated dose, and/or recommended phase 2 dose (primary) and to evaluate preliminary efficacy and pharmacokinetics (secondary). Results Sixty‐nine patients were enrolled, including 50 in the dose‐escalation arm and 19 in the dose‐expansion arm. Thrombocytopenia was the most common treatment‐related adverse event and was successfully managed with dose modifications. Clinical activity with prolonged, durable responses were observed, particularly in patients who had neuroendocrine neoplasms. In the dose‐escalation arm, one patient with relapsed/refractory marginal zone lymphoma achieved a complete response (ongoing in cycle 58). In the dose‐expansion arm, three patients with neuroendocrine neoplasms had stable disease after nine or more cycles, including one patient who was in cycle 46 of ongoing treatment. CC‐90011 decreased levels of secreted neuroendocrine peptides chromogranin A, progastrin‐releasing peptide, and RNA expression of the blood pharmacodynamic marker monocyte‐to‐macrophage differentiation–associated. Conclusions The safety profile of CC‐90011 suggested that its reversible mechanism of action may provide an advantage over other irreversible LSD1 inhibitors. The favorable tolerability profile, clinical activity, durable responses, and once‐per‐week dosing support further exploration of CC‐90011 as monotherapy and in combination with other treatments for patients with advanced solid tumors and other malignancies.

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The Histone Demethylase KDM1A Sustains the Oncogenic Potential of MLL-AF9 Leukemia Stem Cells

Cited by 135 publications

References 0 publications

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Lysine-specific demethylase 1 restricts hematopoietic progenitor proliferation and is essential for terminal differentiation

Modulators of histone demethylase JMJD1C selectively target leukemic stem cells

Clinical activity of CC‐90011, an oral, potent, and reversible LSD1 inhibitor, in advanced malignancies

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