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FNDC3B-RARA: A novel fusion gene in variant APL
Acute Promyelocytic Leukemia (APL) is characterized by Promyelocytic Leukemia-Retinoic Acid Receptor Alpha (PML-RARA) fusion transcripts. However, in some cases, Retinoic Acid Receptor Alpha (RARA) can fuse with other genes.
In a Letter to the Editor of Blood, Cheng et al., from the Chinese University of Hong Kong, Hong Kong, report a patient with a variant APL because of a novel Fibronectin Type III Domain Containing 3B-Retinoic Acid Receptor Alpha (FNDC3B-RARA) fusion. Cheng et al. also report on the molecular characterization of the FNDC3B-RARA fusion and its implication in granulocytic differentiation.
Case Presentation
Patient (male, 36 years) presented with symptoms including fatigue, dyspnea, and easy bruising. After complete blood count and Bone Marrow (BM) examination, the patient was diagnosed with APL and immediately administered All-Trans Retinoic Acid (ATRA; 45mg/m2/day). Patient developed Differentiation Syndrome (DS) on day 4 and was then administered 7 + 3 induction chemotherapy and achieved morphological complete remission at day 30. The BM sample collected at diagnosis was analyzed molecularly.
The key results were:
- PML-RARA fusion was not detected, however 72% of BM cells had split RARA signals
- Karyotype performed on the BM sample revealed a 45,C,-Yt(3;17)(q26;q21) variant
- A fusion between exon 24 of FNDC3B, an adipocyte differentiation factor, and exon 3 of RARA was observed
- Two reciprocal RARA-FNDC3B transcripts were detected
- RARA-FNDC3B and FNDC3B-RARA fusion were undetected after consolidation therapy
FNDC3B-RARA fusion was characterized molecularly.
The key results of were:
- Using immunofluorescence, it was found that FNDC3B-RARA was predominantly nuclear
- Compared to RARA, FNDC3B-RARA repressed retinoic acid-response elements more robustly
- Treatment with ATRA strongly stimulated FNDC3B activity at a dose of 10-6M compared to RARA
- Small Interfering RNA (siRNA) knockdown of FNDC3B impaired ATRA-induced NB4 cell (a human APL cell line) differentiation as judged by reduced expression of CD11b and CEBPE expression (terminal granulopoiesis marker)
- Treatment of NB4 cells with FNDC3B siRNAs increased the proliferation of NB4 cells
The authors noted that FNDC3B-RARA fusion is the “13th RARA fusion gene identified” with opposite ATRA responses within the t(3;17) APL subtype.
References