A novel NUP98-JADE2 fusion in a patient with acute myeloid leukemia resembling acute promyelocytic leukemia

• Published in: Blood advances 2022-01, Vol.6 (2), p.410-415
• Main Authors: Cheng, Chi-Keung, Chan, Hoi-Yun, Yung, Yuk-Lin, Wan, Thomas S.K., Leung, Alex W.K., Li, Chi-Kong, Tian, Ke, Chan, Natalie P.H., Cheung, Joyce S., Ng, Margaret H.L.
• Format: Article
• Language: English
• Subjects: Child; Exceptional Case Report; Humans; Leukemia, Myeloid, Acute - diagnosis; Leukemia, Myeloid, Acute - genetics; Leukemia, Promyelocytic, Acute - diagnosis; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - pathology; Nuclear Pore Complex Proteins - genetics; Receptors, Retinoic Acid - genetics; Tretinoin
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2021006064

Acute promyelocytic leukemia (APL) is a specific subtype of acute myeloid leukemia (AML) characterized by block of differentiation at the promyelocytic stage and the presence of PML-RARA fusion. In rare instances, RARA is fused with other partners in variant APL. More infrequently, non-RARA genes are rearranged in AML patients resembling APL. However, the underlying disease pathogenesis in these atypical cases is largely unknown. Here, we report the identification and characterization of a NUP98- JADE2 fusion in a pediatric AML patient showing APL-like morphology and immunophenotype. Mechanistically, we showed that NUP98-JADE2 could impair all-trans retinoic acid (ATRA)-mediated transcriptional control and myeloid differentiation. Intriguingly, NUP98-JADE2 was found to alter the subcellular distribution of wild-type JADE2, whose down-regulation similarly led to attenuated ATRA-induced responses and myeloid activation, suggesting that NUP98-JADE2 may mediate JADE2 inhibition. To our knowledge, this is the first report of a NUP98-non-RAR rearrangement identified in an AML patient mimicking APL. Our findings suggest JADE2 as a novel myeloid player involved in retinoic acid-induced differentiation. Despite lacking a rearranged RARA, our findings implicate that altered retinoic acid signaling by JADE2 disruption may underlie the APL-like features in our case, corroborating the importance of this signaling in APL pathogenesis. •Non-RAR gene rearrangements have been associated with patients with AML resembling APL but the underlying pathogenesis is unclear.•NUP98-JADE2 perturbs wild-type JADE2 and retinoic acid signaling thereby contributing to an APL-like phenotype.