All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16

Dembitz, Vilma; Lalić, Hrvoje; Tomić, Barbara; Smoljo, Tomislav; Batinić, Josip; Dubravčić, Klara; Batinić, Drago; Bedalov, Antonio; Višnjić, Dora

doi:10.1007/s12185-021-03224-5

Cited by 6 publications

(7 citation statements)

References 33 publications

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“…The exception to the 220% standard was CBF acute myeloid leukemia including cytogenetic abnormalities (t [8; 21], or inv [16], or t [16; 16]), NPM1 mutant AML, or acute promyelocyte leukemia; in each case, the diagnosis of acute myeloid leukemia was not dependent of % of blast seen. Occasionally myeloid blasts may also have T-cell or B-cell markers for the identification or may have distinct myeloid and lymphoid populations [ 40 – 43 ]. These AML cases are identified as “mixed phenotypic acute leukemia.” It is still unclear whether it requires simultaneous treatment as acute myeloid leukemia, lymphoblastic leukemia, or both.…”

Section: Discussionmentioning

confidence: 99%

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis

Han

et al. 2022

Journal of Healthcare Engineering

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Purpose. This study aims to determine the influence of targeting araC-resistant acute myeloid leukemia by dual inhibition cyclin-dependent protein kinase (CDK9) and B-cell lymphoma-2 （Bcl-2). Method. The c-Myc inhibitor 10058-F4 and the CDK9 inhibitor AZD4573 were used to determine the cell cycle arrest and apoptosis. Results. 10058-F4 reduces c-Myc protein levels and suppresses HepG2 cell proliferation, possibly by upregulating cyclin-dependent kinase (CDK) inhibitors, p21WAF1, and reducing intracellular alpha-fetal protein (AFP) levels. Conclusion. The combination of AZD4573 and 10058-F4 has a synergistic anti-araC-resistant AML activity, providing a solid database for the aforementioned scientific hypothesis.

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Section: Discussionmentioning

confidence: 99%

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis

Han

et al. 2022

Journal of Healthcare Engineering

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“…Among these hub targets, CDK1 was strongly correlated with CCNB1, and MAPK1 was correlated with CD11b well. Because CCNB1 is an indicator of G2/M cell cycle (Khan et al, 2021), and CD11 b is an indicator of cell differentiation (Dembitz et al, 2021), our results indicate that CDK1 and MAPK1 might play important roles in anti-leukemic activity through G2/M phase cell cycle arrest and cell differentiation.…”

Section: Discussionmentioning

confidence: 74%

Decoding the Mechanism of Shen Qi Sha Bai Decoction in Treating Acute Myeloid Leukemia Based on Network Pharmacology and Molecular Docking

Jia¹,

Jiang²,

Li³

et al. 2021

Front. Cell Dev. Biol.

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Traditional Chinese Medicine (TCM) has been shown to be efficacious in treating leukemia for thousands of years. It has been shown that Shen Qi Sha Bai Decoction (SQSBD) has been extensively used in the treatment of acute myeloid leukemia (AML). However, the mechanism of SQSBD in treating AML remains unclear. In this study, we employed network pharmacology to analyze the potential active components and elucidate molecular mechanism of SQSBD in treating AML. A total of 268 active components were identified from SQSBD, among which 9 key components (Quercetin, luteolin, kaempferol, licochalcone A, formononetin, wogonin, β-sitosterol, oroxylin A, naringenin, and baicalein) were hit by the 6 hub targets (CDK1, MAPK1, JUN, PCNA, HSB1, STAT3) associated with leukemia. Molecular docking showed that two core active components, quercetin and licochalcone A, exhibited the highest component-like properties (DL), and could bind well to CDK1 and MAPK1 protein. The experimental validation of these two components showed that quercetin inhibited cell growth through CDK1 dephosphorylation-mediated cell cycle arrest at G2/M phase in human AML U937 and HL60 cells, and licochalcone A induced cell differentiation in these leukemia cells via activation of MAPK1 and upregulation of CD11b. All these results indicate that SQSBD is effective in the treatment of AML, and quercetin and licochalcone A are the major candidate compounds for AML treatment.

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“…THP-1 cells used in our study are KMT2A-MLLT3 pos cells, and CDK6 was demonstrated to be important for differentiation in KMT2A -rearranged AML cells, but genetic down-regulation of CDK6 in study by Placke et al 39 induced mild G 0 /G 1 arrest associated with differentiation, while we observed an arrest of THP-1 cells in S and G 2 /M-phase. Both U937 and THP-1 cells lack functional p53 40 , and p53-mediated response to DNA damage is known to affect chemotherapy response in AML 41 , 42 . Down-regulation of several other cell cycle regulators, like CDK2 43 or AURKA 44 were found to induce differentiation, as well as upregulation of p21 13 , 31 or accumulation of PU.1 transcription factors 45 .…”

Section: Discussionmentioning

confidence: 99%

Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis

Tomić

Smoljo

Lalić

et al. 2022

Sci Rep

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Acute myeloid leukemia (AML) is characterized by arrested differentiation making differentiation therapy a promising treatment strategy. Recent success of inhibitors of mutated isocitrate dehydrogenase (IDH) invigorated interest in differentiation therapy of AML so that several new drugs have been proposed, including inhibitors of dihydroorotate dehydrogenase (DHODH), an enzyme in pyrimidine synthesis. Cytarabine, a backbone of standard AML therapy, is known to induce differentiation at low doses, but the mechanism is not completely elucidated. We have previously reported that 5-aminoimidazole-4-carboxamide ribonucleoside (AICAr) and brequinar, a DHODH inhibitor, induced differentiation of myeloid leukemia by activating the ataxia telangiectasia and Rad3-related (ATR)/checkpoint kinase 1 (Chk1) via pyrimidine depletion. In this study, using immunoblotting, flow cytometry analyses, pharmacologic inhibitors and genetic inactivation of Chk1 in myeloid leukemia cell lines, we show that low dose cytarabine induces differentiation by activating Chk1. In addition, cytarabine induces differentiation ex vivo in a subset of primary AML samples that are sensitive to AICAr and DHODH inhibitor. The results of our study suggest that leukemic cell differentiation stimulated by low doses of cytarabine depends on the activation of Chk1 and thus shares the same pathway as pyrimidine synthesis inhibitors.

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All-trans retinoic acid induces differentiation in primary acute myeloid leukemia blasts carrying an inversion of chromosome 16

Cited by 6 publications

References 33 publications

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis

Targeting AraC-Resistant Acute Myeloid Leukemia by Dual Inhibition of CDK9 and Bcl-2: A Systematic Review and Meta-Analysis

Decoding the Mechanism of Shen Qi Sha Bai Decoction in Treating Acute Myeloid Leukemia Based on Network Pharmacology and Molecular Docking

Cytarabine-induced differentiation of AML cells depends on Chk1 activation and shares the mechanism with inhibitors of DHODH and pyrimidine synthesis

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