FOXM1-AKT Positive Regulation Loop Provides Venetoclax Resistance in AML

Forkhead box protein M1 (FOXM1) is a crucial regulator of cancer development and chemoresistance. It is often overexpressed in acute myeloid leukemia (AML) and is associated with poor survival and reduced efficacy of cytarabine therapy. Molecular mechanisms underlying high FOXM1 expression levels in malignant cells are still unclear. Here we demonstrate that AKT and FOXM1 constitute a positive autoregulatory loop in AML cells that sustains high activity of both pro-oncogenic regulators. Inactivation of either AKT or FOXM1 signaling results in disruption of whole loop, coordinated suppression of FOXM1 or AKT, respectively, and similar transcriptomic changes. AML cells with inhibited AKT activity or stable FOXM1 knockdown display increase in HOXA genes expression and BCL2L1 suppression that are associated with prominent sensitization to treatment with Bcl-2 inhibitor venetoclax. Taken together, our data indicate that AKT and FOXM1 in AML cells should not be evaluated as single independent regulators but as two parts of a common FOXM1-AKT positive feedback circuit. We also report for the first time that FOXM1 inactivation can overcome AML venetoclax resistance. Thus, targeting FOXM1-AKT loop may open new possibilities in overcoming AML drug resistance and improving outcomes for AML patients.

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Genetic Screening for Potential New Targets in Chronic Myeloid Leukemia Based on Drosophila Transgenic for Human BCR-ABL1

Cancers ◽

10.3390/cancers13020293 ◽

2021 ◽

Vol 13 (2) ◽

pp. 293

Author(s):

Marco Lo Iacono ◽

Elisabetta Signorino ◽

Jessica Petiti ◽

Monica Pradotto ◽

Chiara Calabrese ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Genetic Screening ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Disease Onset ◽

Philadelphia Chromosome ◽

Myeloproliferative Neoplasm ◽

Transforming Activity ◽

Tight Connection ◽

First Time

Chronic myeloid leukemia is a myeloproliferative neoplasm characterized by the presence of the Philadelphia chromosome that originates from the reciprocal translocation t(9;22)(q34;q11.2) and encodes for the constitutively active tyrosine kinase protein BCR-ABL1 from the Breakpoint Cluster Region (BCR) sequence and the Abelson (ABL1) gene. Despite BCR-ABL1 being one of the most studied oncogenic proteins, some molecular mechanisms remain enigmatic, and several of the proteins, acting either as positive or negative BCR-ABL1 regulators, are still unknown. The Drosophila melanogaster represents a powerful tool for genetic investigations and a promising model to study the BCR-ABL1 signaling pathway. To identify new components involved in BCR-ABL1 transforming activity, we conducted an extensive genetic screening using different Drosophila mutant strains carrying specific small deletions within the chromosomes 2 and 3 and the gmrGal4,UAS-BCR-ABL1 4M/TM3 transgenic Drosophila as the background. From the screening, we identified several putative candidate genes that may be involved either in sustaining chronic myeloid leukemia (CML) or in its progression. We also identified, for the first time, a tight connection between the BCR-ABL1 protein and Rab family members, and this correlation was also validated in CML patients. In conclusion, our data identified many genes that, by interacting with BCR-ABL1, regulate several important biological pathways and could promote disease onset and progression.

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ZC3H15 promotes glioblastoma progression through regulating EGFR stability

Cell Death and Disease ◽

10.1038/s41419-021-04496-9 ◽

2022 ◽

Vol 13 (1) ◽

Author(s):

Jianbing Hou ◽

Minghao Xu ◽

Hongyu Gu ◽

Dakun Pei ◽

Yudong Liu ◽

...

Keyword(s):

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Biological Significance ◽

Protein Stabilization ◽

Migration And Invasion ◽

Egfr Signaling ◽

Inhibitory Effects ◽

Poor Survival ◽

Cellular Processes ◽

Egfr Signaling Pathway

AbstractZinc finger CCCH-type containing 15 (ZC3H15), a highly conserved protein involved in several cellular processes, which was responsible for tumorigenesis and may be a promising marker in myeloid leukemia (AML) and hepatocellular carcinoma (HCC). However, little is known about the biological significance and molecular mechanisms of ZC3H15 in GBM. In this study, we revealed that ZC3H15 was overexpressed in GBM and high ZC3H15 expression was associated with poor survival of patients with GBM. We found that ZC3H15 promoted the proliferation, migration, invasion, and tumorigenesis of GBM cells by activating the EGFR signaling pathway. We also revealed that ZC3H15 reduced EGFR ubiquitination, which was responsible for EGFR protein stabilization. In addition, we demonstrated that ZC3H15 inhibited the transcription of CBL, which was an E3 ubiquitin ligase for EGFR proteasomal degradation. And silencing of CBL could partly abrogate the inhibitory effects on cell proliferation, migration, and invasion of GBM cells induced by ZC3H15 knockdown. Thus, our research revealed the important roles of ZC3H15 in GBM development and provided a brand-new insight for improving the treatment of GBMs.

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TAMM HORSFALL PROTEIN: THE MEN BEHIND THE EPONYM

Nephrology (Saint-Petersburg) ◽

10.24884/1561-6274-2019-23-2-117-119 ◽

2019 ◽

Vol 23 (2) ◽

pp. 117-119 ◽

Cited By ~ 1

Author(s):

D. N. Paskalev ◽

B. T. Galunska ◽

D. Petkova-Valkova

Keyword(s):

Viral Replication ◽

Research Team ◽

Molecular Mechanisms ◽

Thick Ascending Limb ◽

Rockefeller Institute ◽

The Usa ◽

Natural Inhibitor ◽

Simplex Virus ◽

First Time ◽

New Protein

Tamm–Horsfall Protein (uromodulin) is named after Igor Tamm and Franc Horsfall Jr who described it for the first time in 1952. It is a glycoprotein, secreted by the cells in the thick ascending limb of the loop of Henle. This protein will perform a number of important pathophysiological functions, including protection against uroinfections, especially caused by E. Сoli, and protection against formation of calcium concernments in the kidney. Igor Tamm (1922-1995) is an outstanding cytologist, virologist and biochemist. He is one of the pioneers in the study of viral replication. He was born in Estonia and died in the USA. In 1964 he was elected for a professorship in Rockefeller Institute for Medical Research, where has been working continuously. Since 1959, he became a head of the virology lab established by his mentor and co-author Franc Horsfall. In the course of studies on the natural inhibitor of viral replication, Tamm and Horsfall isolated and characterized biochemically a new protein named after their names. Franc Lappin Horsfall Jr (1906-1971) was a well-known clinician and virologist with remarkable achievements in internal medicine. He was born and died in the USA. He worked in the Rockefeller Hospital from 1934 to 1960, then in the Center for Cancer Research at the Sloan-Kettering Institute. Here he was a leader of a research team studying the molecular mechanisms of immunity, the effects of chemotherapy with benzimidazole compounds (together with I. Tamm), coxsackie viruses, herpes simplex virus, etc.

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FOXC1 in cancer development and therapy: deciphering its emerging and divergent roles

Therapeutic Advances in Medical Oncology ◽

10.1177/1758834017742576 ◽

2017 ◽

Vol 9 (12) ◽

pp. 797-816 ◽

Cited By ~ 36

Author(s):

Zhi Yang ◽

Shuai Jiang ◽

Yicheng Cheng ◽

Tian Li ◽

Wei Hu ◽

...

Keyword(s):

Transcriptional Regulator ◽

Cancer Development ◽

Protein Activity ◽

Stem Cell Maintenance ◽

Cancer Migration ◽

Forkhead Box ◽

Pathological Conditions ◽

Clinical Biomarker ◽

Abnormal Cell Proliferation ◽

Cell Maintenance

Forkhead box C1 (FOXC1) is an essential member of the forkhead box transcription factors and has been highlighted as an important transcriptional regulator of crucial proteins associated with a wide variety of carcinomas. FOXC1 regulates tumor-associated genes and is regulated by multiple pathways that control its mRNA expression and protein activity. Aberrant FOXC1 expression is involved in diverse tumorigenic processes, such as abnormal cell proliferation, cancer stem cell maintenance, cancer migration, and angiogenesis. Herein, we review the correlation between the expression of FOXC1 and tumor behaviors. We also summarize the mechanisms of the regulation of FOXC1 expression and activity in physiological and pathological conditions. In particular, we focus on the pathological processes of cancer targeted by FOXC1 and discuss whether FOXC1 is good or detrimental during tumor progression. Moreover, FOXC1 is highlighted as a clinical biomarker for diagnosis or prognosis in various human cancers. The information reviewed here should assist in experimental designs and emphasize the potential of FOXC1 as a therapeutic target for cancer.

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MicroRNAs and Stem-like Properties: The Complex Regulation Underlying Stemness Maintenance and Cancer Development

Biomolecules ◽

10.3390/biom11081074 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1074

Author(s):

Giuseppina Divisato ◽

Silvia Piscitelli ◽

Mariantonietta Elia ◽

Emanuela Cascone ◽

Silvia Parisi

Keyword(s):

Stem Cells ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Embryonic Stem ◽

Cell Types ◽

Cancer Development ◽

Special Focus ◽

Self Renewal ◽

Mesenchymal Transition ◽

Different Cell Types

Embryonic stem cells (ESCs) have the extraordinary properties to indefinitely proliferate and self-renew in culture to produce different cell progeny through differentiation. This latter process recapitulates embryonic development and requires rounds of the epithelial–mesenchymal transition (EMT). EMT is characterized by the loss of the epithelial features and the acquisition of the typical phenotype of the mesenchymal cells. In pathological conditions, EMT can confer stemness or stem-like phenotypes, playing a role in the tumorigenic process. Cancer stem cells (CSCs) represent a subpopulation, found in the tumor tissues, with stem-like properties such as uncontrolled proliferation, self-renewal, and ability to differentiate into different cell types. ESCs and CSCs share numerous features (pluripotency, self-renewal, expression of stemness genes, and acquisition of epithelial–mesenchymal features), and most of them are under the control of microRNAs (miRNAs). These small molecules have relevant roles during both embryogenesis and cancer development. The aim of this review was to recapitulate molecular mechanisms shared by ESCs and CSCs, with a special focus on the recently identified classes of microRNAs (noncanonical miRNAs, mirtrons, isomiRs, and competitive endogenous miRNAs) and their complex functions during embryogenesis and cancer development.

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Differential Morpho-Physiological and Transcriptomic Responses to Heat Stress in Two Blueberry Species

International Journal of Molecular Sciences ◽

10.3390/ijms22052481 ◽

2021 ◽

Vol 22 (5) ◽

pp. 2481

Author(s):

Jodi Callwood ◽

Kalpalatha Melmaiee ◽

Krishnanand P. Kulkarni ◽

Amaranatha R. Vennapusa ◽

Diarra Aicha ◽

...

Keyword(s):

Heat Stress ◽

Molecular Mechanisms ◽

Stomatal Closure ◽

Enrichment Analysis ◽

Leaf Size ◽

Vaccinium Corymbosum ◽

Climatic Conditions ◽

Differentially Expressed ◽

Transcriptomic Changes ◽

Go Terms

Blueberries (Vaccinium spp.) are highly vulnerable to changing climatic conditions, especially increasing temperatures. To gain insight into mechanisms underpinning the response to heat stress, two blueberry species were subjected to heat stress for 6 and 9 h at 45 °C, and leaf samples were used to study the morpho-physiological and transcriptomic changes. As compared with Vaccinium corymbosum, Vaccinium darrowii exhibited thermal stress adaptation features such as small leaf size, parallel leaf orientation, waxy leaf coating, increased stomatal surface area, and stomatal closure. RNAseq analysis yielded ~135 million reads and identified 8305 differentially expressed genes (DEGs) during heat stress against the control samples. In V. corymbosum, 2861 and 4565 genes were differentially expressed at 6 and 9 h of heat stress, whereas in V. darrowii, 2516 and 3072 DEGs were differentially expressed at 6 and 9 h, respectively. Among the pathways, the protein processing in the endoplasmic reticulum (ER) was the highly enriched pathway in both the species: however, certain metabolic, fatty acid, photosynthesis-related, peroxisomal, and circadian rhythm pathways were enriched differently among the species. KEGG enrichment analysis of the DEGs revealed important biosynthesis and metabolic pathways crucial in response to heat stress. The GO terms enriched in both the species under heat stress were similar, but more DEGs were enriched for GO terms in V. darrowii than the V. corymbosum. Together, these results elucidate the differential response of morpho-physiological and molecular mechanisms used by both the blueberry species under heat stress, and help in understanding the complex mechanisms involved in heat stress tolerance.

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Programme for Harmonization to the International Scale in Latin America for BCR-ABL1 quantification in CML patients: findings and recommendations

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-1283 ◽

2020 ◽

Vol 58 (12) ◽

pp. 2025-2035

Author(s):

María Sol Ruiz ◽

María Belén Sánchez ◽

Yuly Masiel Vera Contreras ◽

Evangelina Agrielo ◽

Marta Alonso ◽

...

Keyword(s):

Latin America ◽

Myeloid Leukemia ◽

World Health ◽

Molecular Response ◽

Limit Of Quantification ◽

International Scale ◽

Deep Molecular Response ◽

Health Organization ◽

First Time

AbstractObjectivesThe quantitation of BCR-ABL1 mRNA is mandatory for chronic myeloid leukemia (CML) patients, and RT-qPCR is the most extensively used method in testing laboratories worldwide. Nevertheless, substantial variation in RT-qPCR results makes inter-laboratory comparability hard. To facilitate inter-laboratory comparative assessment, an international scale (IS) for BCR-ABL1 was proposed.MethodsThe laboratory-specific conversion factor (CF) to the IS can be derived from the World Health Organization (WHO) genetic reference panel; however, this material is limited to the manufacturers to produce and calibrate secondary reference reagents. Therefore, we developed secondary reference calibrators, as lyophilized cellular material, aligned to the IS. Our purpose was both to re-evaluate the CF in 18 previously harmonized laboratories and to propagate the IS to new laboratories.ResultsOur field trial including 30 laboratories across Latin America showed that, after correction of raw BCR-ABL1/ABL1 ratios using CF, the relative mean bias was significantly reduced. We also performed a follow-up of participating laboratories by annually revalidating the process; our results support the need for continuous revalidation of CFs. All participating laboratories also received a calibrator to determine the limit of quantification (LOQ); 90% of them could reproducibly detect BCR-ABL1, indicating that these laboratories can report a consistent deep molecular response. In addition, aiming to investigate the variability of BCR-ABL1 measurements across different RNA inputs, we calculated PCR efficiency for each individual assay by using different amounts of RNA.ConclusionsIn conclusion, for the first time in Latin America, we have successfully organized a harmonization platform for BCR-ABL1 measurement that could be of immediate clinical benefit for monitoring the molecular response of patients in low-resource regions.

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Combining QTL Mapping and Gene Expression Analysis to Elucidate the Genetic Control of ‘Crumbly’ Fruit in Red Raspberry (Rubus idaeus L.)

Agronomy ◽

10.3390/agronomy11040794 ◽

2021 ◽

Vol 11 (4) ◽

pp. 794

Author(s):

Luca M. Scolari ◽

Robert D. Hancock ◽

Pete E. Hedley ◽

Jenny Morris ◽

Kay Smith ◽

...

Keyword(s):

Genetic Control ◽

Developmental Disorder ◽

Molecular Mechanisms ◽

Developmental Stages ◽

Microarray Experiment ◽

Rubus Idaeus ◽

Red Raspberry ◽

Genotype By Sequencing ◽

First Time ◽

Selection Of

‘Crumbly’ fruit is a developmental disorder in raspberry that results in malformed and unsaleable fruits. For the first time, we define two distinct crumbly phenotypes as part of this work. A consistent crumbly fruit phenotype affecting the majority of fruits every season, which we refer to as crumbly fruit disorder (CFD) and a second phenotype where symptoms vary across seasons as malformed fruit disorder (MFD). Here, segregation of crumbly fruit of the MFD phenotype was examined in a full-sib family and three QTL (Quantitative Trait Loci) were identified on a high density GbS (Genotype by Sequencing) linkage map. This included a new QTL and more accurate location of two previously identified QTLs. A microarray experiment using normal and crumbly fruit at three different developmental stages identified several genes that were differentially expressed between the crumbly and non-crumbly phenotypes within the three QTL. Analysis of gene function highlighted the importance of processes that compromise ovule fertilization as triggers of crumbly fruit. These candidate genes provided insights regarding the molecular mechanisms involved in the genetic control of crumbly fruit in red raspberry. This study will contribute to new breeding strategies and diagnostics through the selection of molecular markers associated with the crumbly trait.

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Analysis of a Preliminary microRNA Expression Signature in a Human Telangiectatic Osteogenic Sarcoma Cancer Cell Line

International Journal of Molecular Sciences ◽

10.3390/ijms22031163 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1163

Author(s):

Gaia Palmini ◽

Cecilia Romagnoli ◽

Simone Donati ◽

Roberto Zonefrati ◽

Gianna Galli ◽

...

Keyword(s):

Cell Line ◽

Molecular Mechanisms ◽

Osteogenic Sarcoma ◽

Cancer Cell Line ◽

Microscopic Features ◽

In Vitro Establishment ◽

Profile Characteristic ◽

First Time

Telangiectatic osteosarcoma (TOS) is an aggressive variant of osteosarcoma (OS) with distinctive radiographic, gross, microscopic features, and prognostic implications. Despite several studies on OS, we are still far from understanding the molecular mechanisms of TOS. In recent years, many studies have demonstrated not only that microRNAs (miRNAs) are involved in OS tumorigenesis, development, and metastasis, but also that the presence in high-grade types of OS of cancer stem cells (CSCs) plays an important role in tumor progression. Despite these findings, nothing has been described previously about the expression of miRNAs and the presence of CSCs in human TOS. Therefore, we have isolated/characterized a putative CSC cell line from human TOS (TOS-CSCs) and evaluated the expression levels of several miRNAs in TOS-CSCs using real-time quantitative assays. We show, for the first time, the existence of CSCs in human TOS, highlighting the in vitro establishment of this unique stabilized cell line and an identification of a preliminary expression of the miRNA profile, characteristic of TOS-CSCs. These findings represent an important step in the study of the biology of one of the most aggressive variants of OS and the role of miRNAs in TOS-CSC behavior.

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Prognostic Impacts of D816V KIT Mutation and Peri-Transplant RUNX1–RUNX1T1 MRD Monitoring on Acute Myeloid Leukemia with RUNX1–RUNX1T1

Cancers ◽

10.3390/cancers13020336 ◽

2021 ◽

Vol 13 (2) ◽

pp. 336

Author(s):

Byung-Sik Cho ◽

Gi-June Min ◽

Sung-Soo Park ◽

Silvia Park ◽

Young-Woo Jeon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Residual Disease ◽

Prognostic Significance ◽

Poor Survival ◽

Hematopoietic Stem ◽

Kit Mutation ◽

Time Points ◽

Post Transplant ◽

Acute Myeloid

The prognostic significance of KIT mutations and optimal thresholds and time points of measurable residual disease (MRD) monitoring for acute myeloid leukemia (AML) with RUNX1-RUNX1T1 remain controversial in the setting of hematopoietic stem cell transplantation (HSCT). We retrospectively evaluated 166 high-risk patients who underwent allogeneic (Allo-HSCT, n = 112) or autologous HSCT (Auto-HSCT, n = 54). D816V KIT mutation, a subtype of exon 17 mutations, was significantly associated with post-transplant relapse and poor survival, while other types of mutations in exons 17 and 8 were not associated with post-transplant relapse. Pre- and post-transplant RUNX1–RUNX1T1 MRD assessments were useful for predicting post-transplant relapse and poor survival with a higher sensitivity at later time points. Survival analysis for each stratified group by D816V KIT mutation and pre-transplant RUNX1–RUNX1T1 MRD status demonstrated that Auto-HSCT was superior to Allo-HSCT in MRD-negative patients without D816V KIT mutation, while Allo-HSCT was superior to Auto-HSCT in MRD-negative patients with D816V KIT mutation. Very poor outcomes of pre-transplant MRD-positive patients with D816V KIT mutation suggested that this group should be treated in clinical trials. Risk stratification by both D816V KIT mutation and RUNX1–RUNX1T1 MRD status will provide a platform for decision-making or risk-adapted therapeutic approaches.

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