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26 pages, 4883 KiB

Open AccessArticle

Imidazo[1,2-b]pyrazole-7-Carboxamide Derivative Induces Differentiation-Coupled Apoptosis of Immature Myeloid Cells Such as Acute Myeloid Leukemia and Myeloid-Derived Suppressor Cells

by Edit Kotogány, József Á. Balog, Lajos I. Nagy, Róbert Alföldi, Valeria Bertagnolo, Federica Brugnoli, András Demjén, Anita K. Kovács, Péter Batár, Gabriella Mezei, Renáta Szabó, Iván Kanizsai, Csaba Varga, László G. Puskás and Gábor J. Szebeni

Int. J. Mol. Sci. 2020, 21(14), 5135; https://doi.org/10.3390/ijms21145135 - 20 Jul 2020

Cited by 9 | Viewed by 4544

Abstract

Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response [...] Read more.

Chemotherapy-induced differentiation of immature myeloid progenitors, such as acute myeloid leukemia (AML) cells or myeloid-derived suppressor cells (MDSCs), has remained a challenge for the clinicians. Testing our imidazo[1,2-b]pyrazole-7-carboxamide derivative on HL-60 cells, we obtained ERK phosphorylation as an early survival response to treatment followed by the increase of the percentage of the Bcl-xl^bright and pAkt^bright cells. Following the induction of Vav1 and the AP-1 complex, a driver of cellular differentiation, FOS, JUN, JUNB, and JUND were elevated on a concentration and time-dependent manner. As a proof of granulocytic differentiation, the cells remained non-adherent, the expression of CD33 decreased; the granularity, CD11b expression, and MPO activity of HL-60 cells increased upon treatment. Finally, viability of HL-60 cells was hampered shown by the depolarization of mitochondria, activation of caspase-3, cleavage of Z-DEVD-aLUC, appearance of the sub-G1 population, and the leakage of the lactate-dehydrogenase into the supernatant. We confirmed the differentiating effect of our drug candidate on human patient-derived AML cells shown by the increase of CD11b and decrease of CD33+, CD7+, CD206+, and CD38^bright cells followed apoptosis (IC₅₀: 80 nM) after treatment ex vivo. Our compound reduced both CD11b+/Ly6C+ and CD11b+/Ly6G+ splenic MDSCs from the murine 4T1 breast cancer model ex vivo. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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14 pages, 3619 KiB

Open AccessArticle

Induction of ER Stress in Acute Lymphoblastic Leukemia Cells by the Deubiquitinase Inhibitor VLX1570

by Paola Pellegrini, Karthik Selvaraju, Elena Faustini, Arjan Mofers, Xiaonan Zhang, Jens Ternerot, Alice Schubert, Stig Linder and Pádraig D′Arcy

Int. J. Mol. Sci. 2020, 21(13), 4757; https://doi.org/10.3390/ijms21134757 - 4 Jul 2020

Cited by 13 | Viewed by 3775

Abstract

The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP [...] Read more.

The proteasome is a validated target of cancer therapeutics. Inhibition of proteasome activity results in the activation of the unfolded protein response (UPR) characterized by phosphorylation of eukaryotic initiation factor 2α (eIF2α), global translational arrest, and increased expression of the proapoptotic CHOP (C/EBP homologous protein) protein. Defects in the UPR response has been reported to result in altered sensitivity of tumor cells to proteasome inhibitors. Here, we characterized the effects of the deubiquitinase (DUB) inhibitor VLX1570 on protein homeostasis, both at the level of the UPR and on protein translation, in acute lymphoblastic leukemia (ALL). Similar to the 20S inhibitor bortezomib, VLX1570 induced accumulation of polyubiquitinated proteins and increased expression of the chaperone Grp78/Bip in ALL cells. Both compounds induced cleavage of PARP (Poly (ADP-ribose) polymerase) in ALL cells, consistent with induction of apoptosis. However, and in contrast to bortezomib, VLX1570 treatment resulted in limited induction of the proapoptotic CHOP protein. Translational inhibition was observed by both bortezomib and VLX1570. We report that in distinction to bortezomib, suppression of translation by VXL1570 occurred at the level of elongation. Increased levels of Hsc70/Hsp70 proteins were observed on polysomes following exposure to VLX1570, possibly suggesting defects in nascent protein folding. Our findings demonstrate apoptosis induction in ALL cells that appears to be uncoupled from CHOP induction, and show that VLX1570 suppresses protein translation by a mechanism distinct from that of bortezomib. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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16 pages, 1933 KiB

Open AccessArticle

The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome

by Wen-Chi Yang, Sheng-Fung Lin, Shu-Chen Wang, Wan-Chi Tsai, Chun-Chieh Wu and Shih-Chi Wu

Int. J. Mol. Sci. 2020, 21(9), 3033; https://doi.org/10.3390/ijms21093033 - 25 Apr 2020

Cited by 5 | Viewed by 3006

Abstract

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of [...] Read more.

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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12 pages, 2267 KiB

Open AccessArticle

The Q-LAMP Method Represents a Valid and Rapid Alternative for the Detection of the BCR-ABL1 Rearrangement in Philadelphia-Positive Leukemias

by Stefania Stella, Enrico Marco Gottardi, Valeria Favout, Eva Barragan Gonzalez, Santa Errichiello, Silvia Rita Vitale, Carmen Fava, Luigia Luciano, Fabio Stagno, Francesco Grimaldi, Lucrezia Pironi, Claudia Sargas Simarro, Paolo Vigneri and Barbara Izzo

Int. J. Mol. Sci. 2019, 20(24), 6106; https://doi.org/10.3390/ijms20246106 - 4 Dec 2019

Cited by 8 | Viewed by 3607

Abstract

Molecular detection of the BCR-ABL1 fusion transcripts is necessary for the genetic confirmation of a chronic myeloid leukemia diagnosis and for the risk classification of acute lymphoblastic leukemia. BCR-ABL1 mRNAs are usually identified using a conventional RT-PCR technique according to the BIOMED-1 method. [...] Read more.

Molecular detection of the BCR-ABL1 fusion transcripts is necessary for the genetic confirmation of a chronic myeloid leukemia diagnosis and for the risk classification of acute lymphoblastic leukemia. BCR-ABL1 mRNAs are usually identified using a conventional RT-PCR technique according to the BIOMED-1 method. In this study, we evaluated 122 BCR-ABL1-positive samples with the Q-LAMP assay to establish if this technology may represent a valid alternative to the qualitative BIOMED-1 PCR technique usually employed for the detection and the discrimination of the common BCR-ABL1 transcripts (p190 and p210 isoforms). We found a 100% concordance rate between the two methods. Specifically, the p190- and p210-positive samples were amplified by Q-LAMP with a median threshold time (Tt) of 26.70 min (range: 24.45–31.80 min) and 20.26 min (range: 15.25-34.57 min), respectively. A median time of 19.63 was observed in samples displaying both (e13a2/e14a2) p210 isoforms. Moreover, the Q-LAMP assay allowed recognition of the BCR-ABL1 e13a2 and e14a2 isoforms (median Tts 18.48 for e13a2 vs. 26.08 min for e14a2; p < 0.001). Finally, 20 samples harboring rare BCR-ABL1 isoforms (e1a3, e13a3, e14a3, and e19a2) were correctly identified by the Q-LAMP assay. We conclude that the Q-LAMP assay may represent a faster and valid alternative to the qualitative BIOMED-1 RT-PCR for the diagnosis at BCR-ABL1-positive leukemias, especially when samples are analyzed in centers with restricted resources and/or limited technical expertise. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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Review

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21 pages, 1073 KiB

Open AccessReview

Recent Advances in the Molecular Biology of Systemic Mastocytosis: Implications for Diagnosis, Prognosis, and Therapy

by Margherita Martelli, Cecilia Monaldi, Sara De Santis, Samantha Bruno, Manuela Mancini, Michele Cavo and Simona Soverini

Int. J. Mol. Sci. 2020, 21(11), 3987; https://doi.org/10.3390/ijms21113987 - 2 Jun 2020

Cited by 20 | Viewed by 5111

Abstract

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing [...] Read more.

In recent years, molecular characterization and management of patients with systemic mastocytosis (SM) have greatly benefited from the application of advanced technologies. Highly sensitive and accurate assays for KIT D816V mutation detection and quantification have allowed the switch to non-invasive peripheral blood testing for patient screening; allele burden has prognostic implications and may be used to monitor therapeutic efficacy. Progress in genetic profiling of KIT, together with the use of next-generation sequencing panels for the characterization of associated gene mutations, have allowed the stratification of patients into three subgroups differing in terms of pathogenesis and prognosis: (i) patients with mast cell-restricted KIT D816V; (ii) patients with multilineage KIT D816V-involvement; (iii) patients with “multi-mutated disease”. Thanks to these findings, new prognostic scoring systems combining clinical and molecular data have been developed. Finally, non-genetic SETD2 histone methyltransferase loss of function has recently been identified in advanced SM. Assessment of SETD2 protein levels and activity might provide prognostic information and has opened new research avenues exploring alternative targeted therapeutic strategies. This review discusses how progress in recent years has rapidly complemented previous knowledge improving the molecular characterization of SM, and how this has the potential to impact on patient diagnosis and management. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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25 pages, 675 KiB

Open AccessReview

Digital PCR: A Reliable Tool for Analyzing and Monitoring Hematologic Malignancies

by Nicoletta Coccaro, Giuseppina Tota, Luisa Anelli, Antonella Zagaria, Giorgina Specchia and Francesco Albano

Int. J. Mol. Sci. 2020, 21(9), 3141; https://doi.org/10.3390/ijms21093141 - 29 Apr 2020

Cited by 38 | Viewed by 6332

Abstract

The digital polymerase chain reaction (dPCR) is considered to be the third-generation polymerase chain reaction (PCR), as it yields direct, absolute and precise measures of target sequences. dPCR has proven particularly useful for the accurate detection and quantification of low-abundance nucleic acids, highlighting [...] Read more.

The digital polymerase chain reaction (dPCR) is considered to be the third-generation polymerase chain reaction (PCR), as it yields direct, absolute and precise measures of target sequences. dPCR has proven particularly useful for the accurate detection and quantification of low-abundance nucleic acids, highlighting its advantages in cancer diagnosis and in predicting recurrence and monitoring minimal residual disease, mostly coupled with next generation sequencing. In the last few years, a series of studies have employed dPCR for the analysis of hematologic malignancies. In this review, we will summarize these findings, attempting to focus on the potential future perspectives of the application of this promising technology. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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23 pages, 12194 KiB

Open AccessReview

Mechanisms of Disease Progression and Resistance to Tyrosine Kinase Inhibitor Therapy in Chronic Myeloid Leukemia: An Update

by Luana Bavaro, Margherita Martelli, Michele Cavo and Simona Soverini

Int. J. Mol. Sci. 2019, 20(24), 6141; https://doi.org/10.3390/ijms20246141 - 5 Dec 2019

Cited by 66 | Viewed by 10279

Abstract

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) [...] Read more.

Chronic myeloid leukemia (CML) is characterized by the presence of the BCR-ABL1 fusion gene, which encodes a constitutive active tyrosine kinase considered to be the pathogenic driver capable of initiating and maintaining the disease. Despite the remarkable efficacy of tyrosine kinase inhibitors (TKIs) targeting BCR-ABL1, some patients may not respond (primary resistance) or may relapse after an initial response (secondary resistance). In a small proportion of cases, development of resistance is accompanied or shortly followed by progression from chronic to blastic phase (BP), characterized by a dismal prognosis. Evolution from CP into BP is a multifactorial and probably multistep phenomenon. Increase in BCR-ABL1 transcript levels is thought to promote the onset of secondary chromosomal or genetic defects, induce differentiation arrest, perturb RNA transcription, editing and translation that together with epigenetic and metabolic changes may ultimately lead to the expansion of highly proliferating, differentiation-arrested malignant cells. A multitude of studies over the past two decades have investigated the mechanisms underlying the closely intertwined phenomena of drug resistance and disease progression. Here, we provide an update on what is currently known on the mechanisms underlying progression and present the latest acquisitions on BCR-ABL1-independent resistance and leukemia stem cell persistence. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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19 pages, 265 KiB

Open AccessReview

The Role of Measurable Residual Disease (MRD) in Hematopoietic Stem Cell Transplantation for Hematological Malignancies Focusing on Acute Leukemia

by Anna Czyz and Arnon Nagler

Int. J. Mol. Sci. 2019, 20(21), 5362; https://doi.org/10.3390/ijms20215362 - 28 Oct 2019

Cited by 32 | Viewed by 4888

Abstract

The significance of measurable residual disease (MRD) in hematopoietic stem cell transplantation (HSCT) is well recognized in different hematological malignancies, but the evidence indicate that pre-transplant MRD status is of particular importance in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In [...] Read more.

The significance of measurable residual disease (MRD) in hematopoietic stem cell transplantation (HSCT) is well recognized in different hematological malignancies, but the evidence indicate that pre-transplant MRD status is of particular importance in acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). In ALL, inadequate response at the level of MRD is a commonly accepted risk factor for relapse and thus an indication for allogeneic HSCT. Similarly, growing evidence from the literature strongly suggest that MRD detected by multiparameter flow cytometry or molecular techniques should be also used for risk stratification in AML at the time of HSCT. Despite the well-defined association of MRD and outcomes of HSCT in acute leukemias, there are still many open issues such as the role of additional pre-transplant consolidation for MRD eradication, the ability of HSCT to overcome negative influence of MRD positivity on survival, the impact of conditioning regimen intensity on MRD clearance post HSCT, and transplantation outcomes or the selection of optimal donor with regards to MRD status. In addition, the role of MRD assessment in guiding post-transplant maintenance treatment should also be addressed in prospective trials. These open issues mostly awaiting further clinical studies will be discussed in our current review. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

21 pages, 2191 KiB

Open AccessReview

Advances in Molecular Biology and Targeted Therapy of Mantle Cell Lymphoma

by Pavel Klener

Int. J. Mol. Sci. 2019, 20(18), 4417; https://doi.org/10.3390/ijms20184417 - 8 Sep 2019

Cited by 23 | Viewed by 8976

Abstract

Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL [...] Read more.

Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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29 pages, 2114 KiB

Open AccessReview

Immunotherapy-Based Targeting and Elimination of Leukemic Stem Cells in AML and CML

by Peter Valent, Irina Sadovnik, Gregor Eisenwort, Karin Bauer, Harald Herrmann, Karoline V. Gleixner, Axel Schulenburg, Werner Rabitsch, Wolfgang R. Sperr and Dominik Wolf

Int. J. Mol. Sci. 2019, 20(17), 4233; https://doi.org/10.3390/ijms20174233 - 29 Aug 2019

Cited by 43 | Viewed by 7709

Abstract

The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must [...] Read more.

The concept of leukemic stem cells (LSC) has been developed with the idea to explain the clonal hierarchies and architectures in leukemia, and the more or less curative anti-neoplastic effects of various targeted drugs. It is now widely accepted that curative therapies must have the potential to eliminate or completely suppress LSC, as only these cells can restore and propagate the malignancy for unlimited time periods. Since LSC represent a minor cell fraction in the leukemic clone, little is known about their properties and target expression profiles. Over the past few years, several cell-specific immunotherapy concepts have been developed, including new generations of cell-targeting antibodies, antibody–toxin conjugates, bispecific antibodies, and CAR-T cell-based strategies. Whereas such concepts have been translated and may improve outcomes of therapy in certain lymphoid neoplasms and a few other malignancies, only little is known about immunological targets that are clinically relevant and can be employed to establish such therapies in myeloid neoplasms. In the current article, we provide an overview of the immunologically relevant molecular targets expressed on LSC in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML). In addition, we discuss the current status of antibody-based therapies in these malignancies, their mode of action, and successful examples from the field. Full article

(This article belongs to the Special Issue Advances in Molecular Biology and Targeted Therapy of Leukemias 2.0)

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