Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Shen, Na; Yan, Fei; Pang, Jiuxia; Zhao, Na; Gangat, Naseema; Wu, Lai-Chu; Bode, Ann M.; Al‐Kali, Aref; Litzow, Mark R.; Liu, Shujun

doi:10.1158/1078-0432.ccr-17-0235

Cited by 34 publications

(39 citation statements)

References 45 publications

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“…The expression, shRNA and their respective control vectors were introduced into cells using Lipofectamine™ 2000 reagent (Life Technologies #11668-019) as previously reported. 53 – 56 Notably, three shRNAs targeting different regions of each gene were utilized in 1:1:1 ratio (9 μg in total) in 10 × 10 6 cells. The shRNA-transfected cells were selected in RPMI-1640 containing 1 μg/ml puromycin (ThermoFisher #BP2956) for 48 h before further investigations.…”

Section: Methodsmentioning

confidence: 99%

“…Colony-forming assays were performed in MethoCult ® medium (Stem Cell Technologies #03434) as previously reported. 53 – 56 Briefly, the transfected or drug-treated cells were suspended in 0.3 mL of IMDM medium (Stem Cell Technologies #36150), mixed with MethoCult ® medium and then dispensed into 35 mm dishes. Colonies were counted in 9–14 days.…”

Section: Methodsmentioning

confidence: 99%

“…Cell proliferation assays were performed using Cell Counting Kit-8 (CCK-8, Dojindo Molecular Technologies #CK04-11) as previously reported. 54 , 56 , 63 Briefly, the parental and resistant cells (1.5 × 10 4 ) in RPMI-1640 medium (100 µl) were dispensed into 96-well flat-bottomed microplates and drugs were added after 24 h of incubation. The cells were cultured for another 24 or 48 h, and CCK-8 (10 µl) was added to each well.…”

Section: Methodsmentioning

confidence: 99%

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A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

et al. 2018

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N6-methyladenosine (m6A) on mRNAs is critical for various biological processes, yet whether m6A regulates drug resistance remains unknown. Here we show that developing resistant phenotypes during tyrosine kinase inhibitor (TKI) therapy depends on m6A reduction resulting from FTO overexpression in leukemia cells. This deregulated FTO-m6A axis pre-exists in naïve cell populations that are genetically homogeneous and is inducible/reversible in response to TKI treatment. Cells with mRNA m6A hypomethylation and FTO upregulation demonstrate more TKI tolerance and higher growth rates in mice. Either genetic or pharmacological restoration of m6A methylation through FTO deactivation renders resistant cells sensitive to TKIs. Mechanistically, the FTO-dependent m6A demethylation enhances mRNA stability of proliferation/survival transcripts bearing m6A and subsequently leads to increased protein synthesis. Our findings identify a novel function for the m6A methylation in regulating cell fate decision and demonstrate that dynamic m6A methylome is an additional epigenetic driver of reversible TKI-tolerance state, providing a mechanistic paradigm for drug resistance in cancer.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

et al. 2018

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“…In fact, DNMT1A expression can be targeted in leukemic cells by inhibitors of FABP4 (upregulated in AML and stimulates DNMT1A expression in these cells) 14 or by inhibitors of receptor tyrosine kinases. 15 These treatments result in inhibition of tumor growth, induction of cell differentiation, and impairment of leukemic progress in leukemia animal models. 14 , 15 Very interestingly, a recent study provided evidence that MUC1-C, a transmembrane oncoprotein aberrantly expressed in leukemic SCs (where it is coexpressed with DNMT1), drives DNMT1 transcription.…”

Section: Introductionmentioning

confidence: 99%

“… 15 These treatments result in inhibition of tumor growth, induction of cell differentiation, and impairment of leukemic progress in leukemia animal models. 14 , 15 Very interestingly, a recent study provided evidence that MUC1-C, a transmembrane oncoprotein aberrantly expressed in leukemic SCs (where it is coexpressed with DNMT1), drives DNMT1 transcription. 16 Targeting MUC1-C with a specific monoclonal antibody, together with the DNMT1 inhibitor decitabine, markedly reduces DNMT1 expression and impairs the survival of AML cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

Castelli¹,

Pelosi²,

Testa³

2017

OTT

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Acute myeloid leukemia (AML) is a clonal disorder of myeloid progenitors characterized by the acquisition of chromosomal abnormalities, somatic mutations, and epigenetic changes that determine a consistent degree of biological and clinical heterogeneity. Advances in genomic technologies have increasingly shown the complexity and heterogeneity of genetic and epigenetic alterations in AML. Among the genetic alterations occurring in AML, frequent are the genetic alterations at the level of various genes involved in the epigenetic control of the DNA methylome and histone methylome. In fact, genes involved in DNA demethylation (such as DNMT3A, TET2, IDH1, and IDH2) or histone methylation and demethylation (EZH2, MLL, DOT1L) are frequently mutated in primary and secondary AML. Furthermore, some histone demethylases, such as LSD1, are frequently overexpressed in AML. These observations have strongly supported a major role of dysregulated epigenetic regulatory processes in leukemia onset and development. This conclusion was further supported by the observation that mutations in genes encoding epigenetic modifiers, such as DMT3A, ASXL1, TET2, IDH1, and IDH2, are usually acquired early and are present in the founding leukemic clone. These observations have contributed to development of the idea that targeting epigenetic abnormalities could represent a potentially promising strategy for the development of innovative treatments of AML. In this review, we analyze those proteins and their inhibitors that have already reached the first stages of clinical trials in AML, namely the histone methyltransferase DOT1L, the demethylase LSD1, and the MLL-interacting protein menin.

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A phase II study of combination daunorubicin, cytarabine (Ara‐c), and nilotinib (TAsigna) (DATA) in patients newly diagnosed with acute myeloid leukemia with KIT expression

et al. 2023

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Acute myeloid leukemia (AML) is a challenging cancer in terms of achieving and maintaining long‐duration remissions. Many novel therapies have been added to the standard regimen (combining cytarabine and anthracycline “7 + 3”) to achieve such goals. Nilotinib is an oral multikinase inhibitor that is active against KIT tyrosine kinase, an important stem cell target. In this trial, we combined nilotinib with 7 + 3 induction (daunorubicin 60 mg/m2), high‐dose cytarabine consolidation, and subsequently, if the patient was a candidate, for 2 years' maintenance therapy in patients with AML and KIT (CD117) expression. Patients were allowed to proceed to allogeneic hematopoietic cell transplantation (HCT) if deemed necessary. Our primary goal was increased complete remission rate with this combination. Thirty‐four patients (with a median age 58.5 years) were enrolled on a single‐arm phase II bi‐institutional study; 21 (62%) patients achieved remission. The complete remission rate was 78% in evaluable patients. Thirteen of 34 (38%) patients had allogeneic HCT, all thirteen of which are still alive (100%). Common (>20%) grade 3 non‐hematological toxicities included febrile neutropenia, hypophosphatemia, elevated liver enzymes, and hypertension. Only one patient (3%) died in induction due to liver failure, which was thought secondary to daunorubicin. Our current study reveals good outcomes in patients who received HCT and may warrant a larger study to confirm our findings in that specific population.

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Inactivation of Receptor Tyrosine Kinases Reverts Aberrant DNA Methylation in Acute Myeloid Leukemia

Cited by 34 publications

References 45 publications

A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

A dynamic N6-methyladenosine methylome regulates intrinsic and acquired resistance to tyrosine kinase inhibitors

Targeting histone methyltransferase and demethylase in acute myeloid leukemia therapy

A phase II study of combination daunorubicin, cytarabine (Ara‐c), and nilotinib (TAsigna) (DATA) in patients newly diagnosed with acute myeloid leukemia with KIT expression

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