Identification of a Second Acute Promyelocytic Leukemia (APL) Patient with the STAT5b-RARα Fusion Gene among PML-RARα-Negative Eastern Cooperative Oncology Group (ECOG) APL Protocol Registrants.

Abstract

In addition to the PML-RARα fusion gene, which accounts for >98% of APL cases, a common segment of 5′-truncated RARα has been found to fuse with the following 4 alternative genes: promyelocytic leukemia zinc finger (PLZF-RARα), nucleophosmin (NPM-RARα), nuclear mitotic apparatus protein (NUMA-RARα) and signal transducer and activator of transcription 5b (STAT5b-RARα). While recurrent cases of PLZF-RARα and NPM-RARα have been documented, there are only single case reports of NUMA-RARα and STAT5b-RARα. In two Phase III clinical trials, E2491 and C9710, the ECOG registered 10 and 12 presumptive APL patients, respectively, based on initial clinical and cytological assessment, which were negative for PML-RARα by reverse transcriptase-polymerase chain reaction (RT-PCR) testing. In this study, we tested 20/22 of these PML-RARα-negative protocol patients for the presence of the 4 alternative fusion genes by RT-PCR, using the corresponding normal transcripts for the rearranged genes as RNA transcription controls. All specimens were positive for the control gene, while 1 case each was positive for PLZF-RARα or STAT5b-RARα. The karyotypes for these 2 cases, respectively, were 46, XY, t(11:17)(q23;q21) and 46, XY, t(10;11)(q22:q25), i(17)(q10). None of the X-RARα-negative cases had abnormalities of chromosome 17. Immunophenotypically, the PLZF-RARα case was consistent with APL; the STAT5b-RARα case had all features of APL (negative for CD11a, CD18, CD34, HLA-DR) except for weak CD133 expression. These findings imply that it is the RARα rearrangement that prompts the APL immunophenotype. Sequence analysis of the STAT5b-RARα mRNA disclosed the same break/fusion point of the STAT5b gene as the only previously-reported case of STAT5b-RARα-positive APL (Arnould, et al, Hum Mol Genet8, 1741, 1999). Also like the first case (67 years), our STAT5b-RARα patient was an elderly male (57 years). These results suggest that X-RARα fusion genes will rarely be found in the absence of cytogenetic evidence of chromosome 17 abnormalities and establish that STAT5b-RARα, although rare, is a recurrent pathogenetic factor in APL.

Detection of the STAT5B–RARA fusion transcript in acute promyelocytic leukemia with the normal chromosome 17 on G‐banding

“…Gallagher et al. identified one case with STAT5B–RARA in 22 PML – RARA negative APL cases (6). Xu et al.…”

Acute promyelocytic leukemia harboring a STAT5B‐RARA fusion gene and a G596V missense mutation in the STAT5B SH2 domain of the STAT5B‐RARA

“…With a great interest we read the report regarding the APL patient with STAT5B-RARa (3). To date, there are only three reported APL patients who harbor the STAT5B-RARa (3)(4)(5)(6), therefore, clinical features of this particular subtype, response to therapy and its pathogenesis remain to be determined. This study describes the fourth APL patient harboring the STAT5B-RARa.…”

PLZF-RARα, NPM1-RARα, and Other Acute Promyelocytic Leukemia Variants: The PETHEMA Registry Experience and Systematic Literature Review

“…As a distinction to PML-RAR α APL, our study show that variant forms present with higher median WBC counts, and 40-50% could be classified as high-risk according to the Sanz's score. As per the literature review, only IRF2P2-RAR α APL had different features at diagnosis (3 out 5 cases were female and all had WBC < 5 × 10 9 /L) (Table 4) [7,[15][16][17][18][19][20][21][22][23][24][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61]. On the other hand, it has been suggested that CD56 could be frequently expressed in some variant APL forms [2,4], but this could not be confirmed in our series (CD56 available only in 5 patients).…”

“…Overall, 35 additional APL patients with other RAR α fusion genes have been reported as follow: 12 with the signal transducer and activator of transcription 5 beta (STAT5B)-RARα, 6 with Transducin β-like 1 X-linked receptor 1 (TBLR1-RARα), 5 with interferon regulatory factor 2 binding proteins 2 (IRF2P2)-RARα, 2 with factor interacting with PAPOLA and CPSF1 (FIP1L1)-RAR α , 2 with signal transducer and activator of transcription 3 (STAT3)-RAR α , 2 with BCL6 Corepressor (BCOR)-RAR α , and 1 case of nuclear mitotic apparatus protein 1(NuMa1)-RARα, protein Kinase CAMP-Dependent Type I Regulatory Subunit Alpha (PRKAR1A)-RARα, nucleic acid binding protein 1 (NABP1)-RARα, general transcription factor II-I (GTF2I)-RARα, trafficking From ER To Golgi Regulator (TFG)-RARα, and fibronectin Type III Domain Containing 3B (FNDC3B)-RARα (Table 4) [7,[15][16][17][18][19][20][21][22][23][24][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]. Male predominance was noted (25 patients), with variable age at presentation (median 43 years), in 15 out of 30 patients (50%) with WBC > 10 × 10 9 /L.…”

“…The ATO-based regimen was successfully administered in 1 case at relapse [43][44][45][46]. Among STAT5B-RAR α APL, treatment consisted of intensive chemotherapy plus ATRA (in most patients), with 8 out of 12 (67%) CRs and frequent relapse reported [7,[15][16][17][18][19][20][21][22][23][24]49].…”