Retinoids in haematology : a timely revival?

Blood ◽  
2021 ◽  
Author(s):  
Hugues de The ◽  
Cécile Esnault ◽  
Marie-Claude Geoffroy
Keyword(s):  
Nuclear Receptors ◽  
Myeloid Leukemia ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptors ◽  
Hematopoietic Differentiation ◽  
Retinoid Signaling ◽  
Master Genes ◽  
Significant Interest ◽  
Rare Malignancy

The retinoic acid receptors (RARA, RARB, RARG) are ligand-regulated nuclear receptors which act as transcriptional switches. These master genes drew significant interest in the 1990s due to their key roles in embryogenesis and involvement in a rare malignancy, acute promyelocytic leukemia (APL), in which the RARA (and very rarely RARG or RARB) genes are rearranged, underscoring the central role of deregulated retinoid signaling in leukemogenesis. A number of recent provocative observations have revived interest in the roles of retinoids in non-APL acute myeloid leukemia (AMLs), as well as in normal hematopoietic differentiation. Here we review the role of retinoids in hematopoiesis, as well as in the treatment of non-APL AMLs. From this perspective, broader uses of retinoids in the management of hematopoietic tumors is discussed.

scholarly journals NKL-Code in Normal and Aberrant Hematopoiesis

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1961
Author(s):  
Stefan Nagel
Keyword(s):  
Blood Cells ◽  
Myeloid Leukemia ◽  
Expression Patterns ◽  
Homeobox Genes ◽  
Hematopoietic Differentiation ◽  
Oncogenic Potential ◽  
Specific Tumor ◽  
Tumor Types ◽  
Hematopoietic Cell Lines

We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.

scholarly journals The Pleiotropic Role of Retinoic Acid/Retinoic Acid Receptors Signaling: From Vitamin A Metabolism to Gene Rearrangements in Acute Promyelocytic Leukemia

2019 ◽  
Vol 20 (12) ◽  
pp. 2921 ◽  
Author(s):  
Conserva ◽  
Anelli ◽  
Zagaria ◽  
Specchia ◽  
Albano
Keyword(s):  
Retinoic Acid ◽  
Acute Promyelocytic Leukemia ◽  
Chromosomal Rearrangements ◽  
Therapy Response ◽  
Promyelocytic Leukemia ◽  
Retinoic Acid Receptors ◽  
Hematopoietic Stem ◽  
Vitamin A Metabolism ◽  
Hematological Neoplasms

The family of retinoic acid receptors (RARs: RARα, -β, and -γ) has remarkable pleiotropy characteristics, since the retinoic acid/RARs pathway is involved in numerous biological processes not only during embryonic development, but also in the postnatal phase and during adulthood. In this review, we trace the roles of RA/RARs signaling in the immune system (where this pathway has both an immunosuppressive role or is involved in the inflammatory response), in hematopoiesis (enhancing hematopoietic stem cell self-renewal, progenitor cells differentiation or maintaining the bone marrow microenvironment homeostasis), and in bone remodeling (where this pathway seems to have controversial effects on bone formation or osteoclast activation). Moreover, in this review is shown the involvement of RAR genes in multiple chromosomal rearrangements generating different fusion genes in hematological neoplasms, with a particular focus on acute promyelocytic leukemia and its variant subtypes. The effect of different RARs fusion proteins on leukemic transformation, on patients’ outcome, and on therapy response is also discussed.

scholarly journals Oncogenic role of lncRNA CRNDE in acute promyelocytic leukemia and NPM1-mutant acute myeloid leukemia

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Xuefei Ma ◽  
Wei Zhang ◽  
Ming Zhao ◽  
Shufen Li ◽  
Wen Jin ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Colorectal Neoplasia ◽  
Promyelocytic Leukemia ◽  
Promising Target ◽  
Pathogenesis Related ◽  
Differentiation Block ◽  
Acute Myeloid

Abstract The PML/RARα fusion protein acts in concert with cooperative genetic events in the development of acute promyelocytic leukemia (APL). However, oncogenic long non-coding RNAs (lncRNAs) cooperating with PML/RARα remain under-explored. Here, we first identified a set of pathogenesis-related lncRNAs, aberrantly expressed in APL using RNA-seq data from a large cohort of acute myeloid leukemia (AML) patients and normal counterparts. Among the pathogenesis-related lncRNAs, one of the evolutionarily conservative lncRNAs CRNDE (Colorectal Neoplasia Differentially Expressed) drew our attention. We found that CRNDE was highly expressed in the disease state but not in the preleukemic stage of APL, suggesting that CRNDE might be a secondary event coordinating with PML/RARα to promote APL development. Functional analysis showed that CRNDE knockdown induced differentiation and inhibited proliferation of APL cells, and prolonged survival of APL mice. Further mechanistic studies showed that CRNDE elicited its oncogenic effects through binding the miR-181 family and thereby regulating NOTCH2. Finally, we found that high CRNDE expression was also significantly correlated with NPM1 mutations and contributed to the differentiation block in NPM1-mutant AML. Collectively, our findings shed light on the importance of oncogenic lncRNAs in the development of AML and provide a promising target for AML therapy.

scholarly journals AXL receptor tyrosine kinase: a possible therapeutic target in acute promyelocytic leukemia

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Mariam Fatima ◽  
Salik Javed Kakar ◽  
Fazal Adnan ◽  
Khalid Khan ◽  
Afsar Ali Mian ◽  
...  
Keyword(s):  
Retinoic Acid ◽  
Tyrosine Kinase ◽  
Acute Promyelocytic Leukemia ◽  
Receptor Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Target Genes ◽  
Retinoic Acid Receptor ◽  
Promyelocytic Leukemia ◽  
Axl Receptor Tyrosine Kinase

Abstract Background Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients. AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing β-catenin in the Wnt/β-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL. Methods and results By using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of β-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05). Conclusion Our results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.

Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

2019 ◽  
Vol XIV (1) ◽  
Author(s):  
A.M. Radzhabova ◽  
S.V. Voloshin ◽  
I.S. Martynkevich ◽  
A.A. Kuzyaeva ◽  
V.A. Shuvaev ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Course Of Disease ◽  
Acute Myeloid

A REVIEW ON THE ROLE OF TYROSINE KINASE INHIBITORS AVAILABLE FOR THE MANAGEMENT OF CHRONIC MYELOID LEUKEMIA

2020 ◽  
Vol 7 (2) ◽  
pp. 205-211
Author(s):  
Kaynat Fatima ◽  
Syed Tasleem Raza ◽  
Ale Eba ◽  
Sanchita Srivastava ◽  
Farzana Mahdi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Protein Kinases ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

The function of protein kinases is to transfer a γ-phosphate group from ATP to serine, threonine, or tyrosine residues. Many of these kinases are linked to the initiation and development of human cancer. The recent development of small molecule kinase inhibitors for the treatment of different types of cancer in clinical therapy has proven successful. Significantly, after the G-protein-coupled receptors, protein kinases are the second most active category of drug targets. Imatinib mesylate was the first tyrosine kinase inhibitor (TKI), approved for chronic myeloid leukemia (CML) treatment. Imatinib induces appropriate responses in ~60% of patients; with ~20% discontinuing therapy due to sensitivity, and ~20% developing drug resistance. The introduction of newer TKIs such as, nilotinib, dasatinib, bosutinib, and ponatinib has provided patients with multiple options. Such agents are more active, have specific profiles of side effects and are more likely to reach the necessary milestones. First-line treatment decisions must be focused on CML risk, patient preferences and comorbidities. Given the excellent result, half of the patients eventually fail to seek first-line treatment (due to discomfort or resistance), with many of them needing a third or even further therapy lines. In the present review, we will address the role of tyrosine kinase inhibitors in therapy for chronic myeloid leukemia.

Studying Globalization at Home

2017 ◽  
Author(s):  
Sunil Bhatia
Keyword(s):  
Qualitative Research ◽  
Lived Experience ◽  
Participant Observation ◽  
Cultural Narratives ◽  
Cultural Codes ◽  
Qualitative Approaches ◽  
Interpretive Methods ◽  
Significant Interest ◽  
At Home

This chapter documents the ethnographic context in which the interviews and participant observation were conducted for the study presented in this book. It also situates the study within the context of narrative inquiry and develops arguments about the role of self-reflexivity in doing ethnography at “home” and producing qualitative forms of knowledge that are based on personal, experiential, and cultural narratives. It is argued that there is significant interest in the adoption of interpretive methods or qualitative research in psychology. The qualitative approaches in psychology present a provocative and complex vision of how the key concepts related to describing and interpreting cultural codes, social practices, and lived experience of others are suffused with both poetical and political elements of culture. The epistemological and ontological assumptions undergirding qualitative research reflect multiple “practices of inquiry” and methodologies that have different orientations, assumptions, values, ideologies, and criterion of excellence.

Therapy-related acute myeloid leukemia with t(9;11)(p12;q23) in a patient treated for acute promyelocytic leukemia

2003 ◽  
Vol 4 (4) ◽  
pp. 289-291 ◽  
Author(s):  
Mario Annunziata ◽  
Salvatore Palmieri ◽  
Barbara Pocali ◽  
Mariacarla De Simone ◽  
Luigi Del Vecchio ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Acute Promyelocytic Leukemia ◽  
Myeloid Leukemia ◽  
Promyelocytic Leukemia ◽  
Acute Myeloid
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