Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms

Mughal, Tariq I.; Abdel‐Wahab, Omar; Rampal, Raajit K.; Mesa, Ruben A.; Koschmieder, Steffen; Levine, Ross L.; Hehlmann, Rüdiger; Saglio, Giuseppe; Barbui, Tiziano; Etten, Richard A. Van

doi:10.1080/10428194.2016.1185783

Cited by 5 publications

(5 citation statements)

References 68 publications

(48 reference statements)

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“…In addition, we performed analysis by using K562 chronic myeloid leukemia cell line (CML). CML is a MPN disorder characterized by BCR‐ABL1 fusion gene . HU‐S‐PBMSC did not modify cell proliferation assayed by CFSE dilution analysis (data not shown).…”

Section: Discussionmentioning

confidence: 88%

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

et al. 2019

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Hydroxyurea (HU) is a nonalkylating antineoplastic agent used in the treatment of hematological malignancies. HU is a DNA replication stress inducer, and as such, it may induce a premature senescence‐like cell phenotype; however, its repercussion on bystander cell proliferation has not been revealed so far. Our results indicate that HU strongly inhibited peripheral blood mesenchymal stromal cells (PBMSC) proliferation by cell cycle arrest in S phase, and that, consequently, PBMSC acquire senescence‐related phenotypical changes. HU‐treated PBMSC display increased senescence‐associated β‐galactosidase levels and p16INK4 expression, as well as DNA damage response and genotoxic effects, evidenced by expression of γH2A.X and micronuclei. Moreover, HU‐induced PBMSC senescence is mediated by increased reactive oxygen species (ROS) levels, as demonstrated by the inhibition of senescence markers in the presence of ROS scavenger N‐acetylcysteine and NADPH oxidase inhibitor Apocynin. To determine the HU‐induced bystander effect, we used the JAK2V617F‐positive human erythroleukemia 92.1.7 (HEL) cells. Co‐culture with HU‐induced senescent PBMSC (HU‐S‐PBMSC) strongly inhibited bystander HEL cell proliferation, and this effect is mediated by both ROS and transforming growth factor (TGF)‐β expression. Besides induction of premature senescence, HU educates PBMSC toward an inhibitory phenotype of HEL cell proliferation. Finally, our study contributes to the understanding of the role of HU‐induced PBMSC senescence as a potential adjuvant in hematological malignancy therapies.

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Section: Discussionmentioning

confidence: 88%

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

et al. 2019

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“…The advent of tyrosine kinase inhibitors targeting the leukaemogenic tyrosine kinases offered great hope; however, despite their ability to induce durable cytogenetic and molecular responses, they are rarely curative in chronic myeloid leukaemia (CML) and never in other MPNs. 9 JAK2 inhibitors offer significant benefits in terms of symptom reduction 10 , 11 but few patients display reduced allele burden. 12 , 13 Thus, the development of knowledge of molecular pathogenesis mechanisms for the MPNs offers opportunities to inform potential new treatment strategies.…”

Section: Introductionmentioning

confidence: 99%

Proteomic analysis of JAK2V617F-induced changes identifies potential new combinatorial therapeutic approaches

et al. 2017

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In excess of 90% of patients with polycythaemia vera (PV) express a mutated form of Janus kinase 2 (JAK2), JAK2V617F. Such aberrant proteins offer great potential for the treatment of these diseases; however, inhibitors to JAK2 have had limited success in the clinic in terms of curing the disease. To understand the effects of this oncogene in haematopoietic cells with the aim of improving treatment strategies, we undertook a systematic evaluation of the effects of JAK2V617F expression using proteomics. The effects of JAK2V617F on over 5000 proteins and 2000 nuclear phosphopeptide sites were relatively quantified using either SILAC or eight-channel iTRAQ mass spectrometry. Pathway analysis of the proteins identified as changing indicated disruption to the p53 and MYC signalling pathways. These changes were confirmed using orthogonal approaches. The insight gained from this proteomic analysis led to the formation of hypothesis-driven analysis on inhibitor-mediated effects on primary cells from patients with a JAK2V617F mutation. Simultaneous inhibition of MYC and upregulation of p53 led to the preferential extinction of JAK2V617F-positive CD34+ cells, illustrating a potential therapeutic benefit from combined targeting of p53 and MYC.

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“…Chronic myeloid leukemia (CML) is a dominant type of myeloproliferative neoplasm, accounting for about 15% of newly diagnosed leukemia in adults [26]. The main genetic event causing CML is reciprocal translocation t (9;22)(q34;q11), or Philadelphia chromosome, causing formation of "breakpoint cluster region" (BCR)-"Abelson murine leukemia" (ABL) fusion transcript, which encodes the BCR-ABL oncoprotein with constitutively active tyrosine kinase activity [27].…”

Section: Chronic Myeloid Leukemiamentioning

confidence: 99%

Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia

Gašić

Karan-Djurašević

Pavlovic

et al. 2022

Life

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Leukemia is a heterogenous group of hematological malignancies categorized in four main types (acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL). Several cytogenetic and molecular markers have become a part of routine analysis for leukemia patients. These markers have been used in diagnosis, risk-stratification and targeted therapy application. Recent studies have indicated that numerous regulatory RNAs, such as long non-coding RNAs (lncRNAs), have a role in tumor initiation and progression. When it comes to leukemia, data for lncRNA involvement in its etiology, progression, diagnosis, treatment and prognosis is limited. The aim of this review is to summarize research data on lncRNAs in different types of leukemia, on their expression pattern, their role in leukemic transformation and disease progression. The usefulness of this information in the clinical setting, i.e., for diagnostic and prognostic purposes, will be emphasized. Finally, how particular lncRNAs could be used as potential targets for the application of targeted therapy will be considered.

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Contemporary insights into the pathogenesis and treatment of chronic myeloproliferative neoplasms

Cited by 5 publications

References 68 publications

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

Hydroxyurea‐induced senescent peripheral blood mesenchymal stromal cells inhibit bystander cell proliferation of JAK2V617F‐positive human erythroleukemia cells

Proteomic analysis of JAK2V617F-induced changes identifies potential new combinatorial therapeutic approaches

Diagnostic and Therapeutic Implications of Long Non-Coding RNAs in Leukemia

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