Acute promyelocytic leukemia (APL; FAB type M3)

4 cases to date, 3 male and 1 female patients; ages at diagnosis was documented in 2 cases: 27 and 63 years (Macedo et al., 2005; Chen et al., 2014).

In one patient, data were available: bone marrow cells revealed hypercellularity with 83% hypergranular promyelocytes lacking Auer rods. Immunophenotyping analysis by flow cytometry was positive for myeloperoxidase, CD13, CD9 with partially expressed CD117, CD15, CD33, and CD64; CD34 and HLA-DR were negative (Chen et al., 2014).

The one patient well described in Chenn et al., 2014 (63-year-old male patient) received induction therapy with ATRA, cytarabine, and mitoxantrone but failed to achieve complete remission (58% promyelocytes on day 32). Therapy with ATRA should be suspended on day 24 because of severe pulmonary infection. He was subsequently treated with arsenic trioxide and chemotherapy resulting in complete remission, but 10 months after diagnosis he relapsed with 81% of promyelocytes in bone marrow and died 1 month later (Chen et al., 2014). The female patient reported by Chen et al., 2014 was initially treated with ATRA and daunorubicin and achieved CR on day 36. However, in addition to the t(3;17)(q21;q25) TBL1XR1/RARA, a t(15;17)(q22;q12) PML/RARA transcript was also detected in this patient. In Machedo et al., 2005, the rearrangement t(3;17)(q26.3;q12) was accompanied with a poor outcome. Due to the limited data available regarding patient outcomes, the efficiency of ATRA on APL patients with TBLR1/RARA is unclear.

Variable breakpoints on 3q and 17q, described as: t(3;17)(q26;q21), t(3;17)(q27;q22), t(3;17)(q21;q25) (Chen et al., 2014) (Authors note: the latter may be t(3;17)(q25;q21) ?) and as a t(3;17)(q26;q12) in a patient with unknown gene involved at 3q26 (Macedo et al., 2005).

Part of complex karyotypes in all the 4 patients; recurrent abnormalities were: del(6)q), -7, del(7q) and in 1 patient t(15;17)(q22;q12) with PML/RARA fusion as above mentioned (Chen et al., 2014).

5-TBLR1-3 RARA

In-frame fusion transcript; TBLR1 exon 5 is fused to exon 3 of RARA

Predicted to encode a 545 amino acids (aa) fusion protein, containing a LisH domain (6-32 aa) in the TBLR1 portion and a DNA-binding domain (DBD; 166-250 aa) and a ligand-binding domain (LBD; 270-500 aa) in the RARA portion (B through F domains of RARA) (Chen et al., 2014; Heinen et al., 2016).

The common feature of RARA fusion proteins is the ability to self-associate, forming homodimers. The TBL1XR1/RARA fusion protein is predominantly localized in the nucleus and self-associate into homodimers through its LisH domain and associate with retinoid X receptor alpha into heterodimers. The multimerization of the chimeric protein may be a key factor in interfering with normal signaling leading to diminished transcriptional activity.

TBL1XR1/RARA