SFPQ‐ABL1‐positive B‐cell precursor acute lymphoblastic leukemias

In recent years, a subgroup of B‐cell precursor acute lymphoblastic leukemia (BCP ALL) without an established abnormality (“B‐other”) has been shown to be characterized by rearrangements of ABL1, ABL2, CSF1R, or PDGFRB (a.k.a. ABL‐class genes). Using FISH with probes for these genes, we screened 55 pediatric and 50 adult B‐other cases. Three (6%) of the adult but none of the childhood B‐other cases were positive for ABL‐class aberrations. RT‐PCR and sequencing confirmed a rare SFPQ‐ABL1 fusion in one adult B‐other case with t(1;9)(p34;q34). Only six SFPQ‐ABL1‐positive BCP ALLs have been reported, present case included. A review of these shows that all harbored fusions between exon 9 of SFPQ and exon 4 of ABL1, that the fusion is typically found in adolescents/younger adults without hyperleukocytosis, and that IKZF1 deletions are recurrent. The few patients not treated with tyrosine kinase inhibitors (TKIs) and/or allogeneic stem cell transplantation relapsed, strengthening the notion that TKI should be added to the therapy of SFPQ‐ABL1‐positive BCP ALL.


| Patients
Between 1993 and 2018, a total of 94 pediatric B-other cases were diagnosed at the Departments of Pediatric Oncology and Hematology, Skåne and Linköping University Hospitals, Sweden. Of these, cells in fixative from 55 (59%) cases were available for FISH analyses. The male/ female ratio was 1.4 and the median age was 5 years (range 0-17 years).
Sixty-six adult B-other cases were diagnosed between 1991 and 2017 at the Department of Hematology, Skåne University Hospital, Sweden. Of these, 50 (76%) could be analyzed by FISH. The male/ female ratio was 0.85 and the median age was 44.5 years (range 19-90 years; Table S2). for split signals were 1.3%, 0%, and 1.6% for the ABL1, ABL2, and CSF1R/PDGFRB probes, respectively.

| FISH and RT-PCR
We cannot entirely exclude the possibility that some ABL-class rearrangements were missed by our FISH screening approach due to, for example, small insertions. However, to the best of our knowledge, no ABL-class-fusion positive case has so far been reported to be false FISH negative (https://mitelmandatabase.isb-cgc.org).
The RT-PCR analysis for the SFPQ-ABL1 fusion was performed using the primer sequences published by Hidalgo-Curtis et al. 10 The amplified product was sequenced with the same primers using the BigDye Terminator v1.1 Cycle Sequencing Kit on an ABI-3130 Genetic Analyzer (Applied Biosystems, Foster City, CA).

| RESULTS AND DISCUSSION
No ABL-class rearrangements were found in the samples from the childhood cases (Table S1) and only three (6%) of the adult B-other cases had such an abnormality (Table S2). It is difficult to compare these frequencies with those reported in prior studies because of different NCI risk cohorts or cytogenetic subgroups analyzed and/or different methodologies used. However, our frequencies in B-other cases are on par with previously published series. 7,8,22,[24][25][26][27] Of the three ABL-class-positive adult cases identified, one had a t (1;5)(q22;q33) involving the CSF1R gene and this case has previously been reported to harbor an MEF2D-CSF1R fusion that was responsive to imatinib. 17 One case with a normal karyotype had an ABL1 rearrangement in a low frequency (7.5%) of interphase cells (#28 in Table S2). To provide further support for an ABL1 rearrangement in the latter case, it was also analyzed with the Vysis LSI BCR/ABL Dual  (Table 1). 10,[29][30][31] Apart from being fused to ABL1 in BCP ALL, SFPQ is rearranged, most often as the 5 0 partner, with other genes in some human malignancies: TFE3 in renal cell carcinomas and perivascular epithelioid cell tumors, 32,33 ZFP36L1 and ZFP36L2 in pediatric T-cell ALL, 34,35 and RLF in breast cancer. 36 The exact role of the pre-mRNA splicing factor SFPQ in all these fusion proteins has not been clarified; however, in BCP ALL, it most likely provides the coiled-coil domains that underlie the oligomerization and subsequent activation of the ABL1 kinase. 10 Although the number of SFPQ-ABL1-positive BCP ALL cases reported is low, some general, albeit tentative, conclusions can be drawn. Firstly, in all cases reported to date, exon 9 of SFPQ has been fused to exon 4 of ABL1. Secondly, and as seen in Table 1, all patients have been adolescents/younger adults between the ages of 19 and 34 years who have had some degree of leukocytosis, but not hyperleukocytosis. Unfortunately, detailed immunophenotypes of most published cases have either not been mentioned or only superficially described (Table 1)  supporting their sensitivity to TKI treatment. 8,37,38 In contrast, no such information is available for SFPQ-ABL1. However, of the five patients with SFPQ-ABL1-positive BCP ALL for whom type of treatment was reported, only those receiving TKI and/or undergoing allogeneic stem cell transplantation remained in complete remission 1 at the time of reporting (Table 1); this supports the notion that TKI should be added to the treatment of all SFPQ-ABL1-positive cases.
However, functional studies are needed to substantiate the efficacy of TKI treatment of this particular ABL-class fusion.

CONFLICT OF INTEREST
The authors declare no conflict of interest.

DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new data were created or analyzed in this study.