Abstract
Retinoic acid receptor γ (RARγ) belongs to the nuclear receptor superfamily and shares 90% homology with retinoic acid receptor α (RARα) and retinoic acid receptor β (RARβ). RARA rearrangements are well-known to be involved in acute promyelocytic leukemia (APL), but RARG rearrangements can also resemble this kind of leukemia. In this review we trace the role of RARγ, considering both its physiological and oncogenic contribution; from 2011 to date, nine cases of patients harboring RARG fusions have been reported. These patients showed typical APL features, including the clinical presentation, coagulation abnormalities and morphological features of bone marrow (BM), but are not responsive to APL standard therapy. We stress the urgent need for a better comprehension of the critical role of RARG dysregulation in the leukemogenesis process, since optimum therapy strategies have not yet been established.
Highlights
Acute myeloid leukemia (AML) is a hematologic malignancy that may arise in patients with another hematological disorder already present or after previous therapy, for instance following previous exposure to alkylating agents or DNA topoisomerase inhibitors or radiation (Sill et al, 2011), but most frequently it appears as a de novo malignancy in previously healthy individuals (De Kouchkovsky and Abdul-Hay, 2016)
The aim of this review is to focus on the various emerging cases of acute promyelocytic leukemia (APL) without the RARA gene rearrangement and with the RARG gene rearrangement or dysregulation that presented abnormal promyelocytes fully in accordance with the APL phenotype
Retinoic acid receptor γ (RARγ) is involved in maintaining a balance between the self-renewal and differentiation of hematopoietic stem cells (HSCs) rather than in the granulocytic differentiation
Summary
Acute myeloid leukemia (AML) is a hematologic malignancy that may arise in patients with another hematological disorder already present or after previous therapy, for instance following previous exposure to alkylating agents or DNA topoisomerase inhibitors or radiation (Sill et al, 2011), but most frequently it appears as a de novo malignancy in previously healthy individuals (De Kouchkovsky and Abdul-Hay, 2016). Green et al confirmed that RARγ is a crucial regulatory key for the presence of a healthy BM microenvironment, since mice with conditionally deleted RARG in more primitive limb bud-derived mesenchymal stem cells and their progeny, achieved through the use of Prrx1-Cre, showed alterations in the number of both osteoclasts and osteoblasts, with consequent modifications in the trabecular bone and an abnormal angiogenesis and B lymphopoiesis These results seem to confirm the key role of RARγ in maintaining homeostasis in the various processes that occur in the BM microenvironment (Conserva et al, 2019), such as endochondral bone formation, angiogenesis, osteoclastogenesis and B lymphopoiesis (Green et al, 2018). In recent years, have described various cases of patients carrying translocations involving RARG and showing a leukemic phenotype that resembles APL (Table 1) It seems that RARG, just like RARA, can somehow rearrange and mediate oncogenic effects. The oncogenic potential of NUP98-RARγ was confirmed by retroviral transduction/transformation assay in murine HSCs; the cellular transformation
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