Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Braun, Theodore P.; Coblentz, Cody; Curtiss, Brittany M.; Coleman, Daniel J.; Schonrock, Zachary; Carratt, Sarah A.; Callahan, Rowan; Maniaci, Breanna N.; Druker, Brian J.; Maxson, Julia E.

doi:10.1073/pnas.1918307117

Cited by 25 publications

(27 citation statements)

References 61 publications

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“…Another way in which the JAK-STAT pathway contributes to the pathogenesis of AML is the reliance of leukemic cells on its signaling. AML cells carrying CEBPA or CEBPA/CSF3R mutations are sensitive to the inhibition of the JAK-STAT pathway [97]. Similar sensitivity has been detected in AML cells expressing RUNX1-RUNX1T1 [98].…”

Section: Dysregulation Of Jak-stat Signaling In the Pathogenesis Of Amlsupporting

confidence: 53%

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

Moser¹,

Edtmayer²,

Witalisz-Siepracka³

et al. 2021

Biomedicines

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Aberrant Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling is implicated in the pathogenesis of acute myeloid leukemia (AML), a highly heterogeneous hematopoietic malignancy. The management of AML is complex and despite impressive efforts into better understanding its underlying molecular mechanisms, survival rates in the elderly have not shown a substantial improvement over the past decades. This is particularly due to the heterogeneity of AML and the need for personalized approaches. Due to the crucial role of the deregulated JAK-STAT signaling in AML, selective targeting of the JAK-STAT pathway, particularly constitutively activated STAT3 and STAT5 and their associated upstream JAKs, is of great interest. This strategy has shown promising results in vitro and in vivo with several compounds having reached clinical trials. Here, we summarize recent FDA approvals and current potential clinically relevant inhibitors for AML patients targeting JAK and STAT proteins. This review underlines the need for detailed cytogenetic analysis and additional assessment of JAK-STAT pathway activation. It highlights the ongoing development of new JAK-STAT inhibitors with better disease specificity, which opens up new avenues for improved disease management.

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Section: Dysregulation Of Jak-stat Signaling In the Pathogenesis Of Amlsupporting

confidence: 53%

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

Moser¹,

Edtmayer²,

Witalisz-Siepracka³

et al. 2021

Biomedicines

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“…These results confirm that the drug combination produces greater cytotoxicity than either drug alone. In other molecular subtypes of AML, LSD1 inhibition promotes cell death through differentiation of immature AML blasts 13,[49][50][51][52][53] . Surface expression of the maturation associated marker, CD86, was increased by LSD1 inhibitor alone and to a similar degree when combined with avapritinib (Supplementary Figure 1 E-F).…”

Section: Characterization Of Synergistic Cytotoxicity Following Kit and Lsd1 Inhibitionmentioning

confidence: 99%

PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia

Curtiss

VanCampen

Kong

et al. 2021

Preprint

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Activating mutations in the KIT tyrosine receptor kinase confer an adverse prognosis for patients with acute myeloid leukemia (AML). Successful treatment options are limited, as kinase inhibition monotherapy for AML is often followed by rapid drug resistance. Here we demonstrate that combined KIT and LSD1 inhibition causes increased cytotoxicity and may mitigate the propensity for relapse with kinase inhibition. This combination suppresses MYC at both the transcript and protein level to drive cell cycle exit and cell death. This decreased MYC transcript expression results from a loss of PU.1 binding at a downstream MYC enhancer leading to decreased acetylation at the MYC enhancer and promoter. Additionally, the drug combination inactivates PI3K/AKT/GSK3 signaling to decrease MYC protein stability. Within 24 hours, KIT-mutant AML cells adapt to KIT inhibitor monotherapy by restoring PI3K/AKT activity. However, with the addition of a LSD1 inhibitor, PI3K/AKT activity cannot be restored. Taken together, KIT and LSD1 inhibition cooperatively target MYC activity through altered transcription and modulation of signaling to drive a lasting response. In addition, we validate MYC suppression as a mechanism of synergy between KIT and LSD1 inhibition in KIT-mutant AML patient samples. Collectively, this work provides rational for a clinical trial to assess the efficacy of KIT and LSD1 inhibition in patients with KIT-mutant AML.

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“…LSD1 also has the function of non-histone lysine methylation [ 113 ], which is not discussed here. In addition, many recent studies have shown that LSD1 can be an important molecular target for the treatment of acute myeloid leukemia [ 114 , 115 ], but therapies directly associated with HIFs activity need to be further explored.…”

Section: Epigenetic Regulation Of Hifs Activitymentioning

confidence: 99%

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

Mao

Wang

et al. 2020

J Exp Clin Cancer Res

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Hypoxia is the major influence factor in physiological and pathological courses which are mainly mediated by hypoxia-inducible factors (HIFs) in response to low oxygen tensions within solid tumors. Under normoxia, HIF signaling pathway is inhibited due to HIF-α subunits degradation. However, in hypoxic conditions, HIF-α is activated and stabilized, and HIF target genes are successively activated, resulting in a series of tumour-specific activities. The activation of HIFs, including HIF-1α, HIF-2α and HIF-3α, subsequently induce downstream target genes which leads to series of responses, the resulting abnormal processes or metabolites in turn affect HIFs stability. Given its functions in tumors progression, HIFs have been regarded as therapeutic targets for improved treatment efficacy. Epigenetics refers to alterations in gene expression that are stable between cell divisions, and sometimes between generations, but do not involve changes in the underlying DNA sequence of the organism. And with the development of research, epigenetic regulation has been found to play an important role in the development of tumors, which providing accumulating basic or clinical evidences for tumor treatments. Here, given how little has been reported about the overall association between hypoxic tumors and epigenetics, we made a more systematic review from epigenetic perspective in hope of helping others better understand hypoxia or HIF pathway, and providing more established and potential therapeutic strategies in tumors to facilitate epigenetic studies of tumors.

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Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

Cited by 25 publications

References 61 publications

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

The Ups and Downs of STAT Inhibition in Acute Myeloid Leukemia

PU.1 and MYC transcriptional network defines synergistic drug responses to KIT and LSD1 inhibition in acute myeloid leukemia

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

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