B R I E F R E P O R T
SFPQ-ABL1-positive B-cell precursor acute lymphoblastic
leukemias
Andrea Biloglav
1|
Linda Olsson-Arvidsson
1,2|
Johan Theander
3|
Mikael Behrendtz
4|
Anders Castor
5|
Bertil Johansson
1,21
Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, Lund, Sweden
2
Division of Laboratory Medicine, Department of Clinical Genetics and Pathology, Lund, Sweden
3
Department of Hematology, Skåne University Hospital, Lund, Sweden
4
Department of Pediatrics, Linköping University Hospital, Linköping, Sweden 5
Department of Pediatrics, Skåne University Hospital, Lund, Sweden
Correspondence
Andrea Biloglav, Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, SE 221 84 Lund, Sweden. Email: andrea.biloglav@med.lu.se Funding information
Swedish Childhood Cancer Foundation, Grant/ Award Number: PR2018-0004; Swedish Cancer Society, Grant/Award Number: CAN 2017/291; Swedish Research Council, Grant/ Award Number: 2016-01084; Governmental Funding of Clinical Research within the National Health Service, Grant/Award Number: Not applicaple; Vetenskapsrådet, Grant/Award Number: 2016-01084
Abstract
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
character-ized 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
hyper-leukocytosis, 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.
K E Y W O R D S
B-cell precursor acute lymphoblastic leukemia, SFPQ-ABL1 fusion, t(1;9)(p34;q34)
1
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I N T R O D U C T I O N
B-cell precursor acute lymphoblastic leukemias (BCP ALL) without any established abnormalities, such as characteristic fusion genes and
ploidy groups, are now often denoted B-other.1Recent studies of
B-other cases, applying whole transcriptome and genome sequencing, have further sub-grouped this clinically and genetically highly hetero-geneous entity, identifying chimeric genes with important diagnostic and prognostic implications, for example fusions involving tyrosine kinase genes (apart from BCR-ABL1) that are present in a subgroup of
BCR-ABL1-like/Ph-like ALL.1-7
Tyrosine kinase rearrangements in Ph-like ALL (“ABL-class fusions”)
mainly involve ABL1 (ABL proto-oncogene 1, non-receptor tyrosine kinase at 9q34.12), ABL2 (ABL proto-oncogene 2, non-receptor tyro-sine kinase; 1q25.2), CSF1R (colony stimulating factor 1 receptor; 5q32), and PDGFRB (platelet derived growth factor receptor beta;
5q32).5,8Several 50 partner genes, apart from BCR, are known to be
rearranged with the 30parts of these ABL-class genes in BCP ALL; they
currently comprise 13 with ABL1 (CENPC, ETV6, FOXP1, INPP5D, LSM14A, NUP153, NUP214, RANBP2, RCSD1, SFPQ, SNX1, SNX2, and ZMIZ1), four with ABL2 (ETV6, PAG1, RCSD1, and ZC3HAV1), three with CSF1R (MEF2D, SSBP2, and TBL1XR1), and nine with PDGFRB (ATF7IP,
Received: 19 December 2019 Revised: 3 April 2020 Accepted: 10 April 2020 DOI: 10.1002/gcc.22852
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2020 The Authors. Genes, Chromosomes & Cancer published by Wiley Periodicals, Inc.
CD74, EBFI, ETV6, SATB1, SSBP2, TNIP1, ZEB2, and ZMYND8).4,5,9-22
The general features of these fusions are that the 50 partner gene
encodes a protein with a dimerization domain and that the 30 part of
the ABL-class gene codes for an intact tyrosine kinase.8
There is ample evidence that many ABL-class-positive BCP ALLs
respond to tyrosine kinase inhibitors (TKI).5,8Thus, detection of
ABL-class rearrangements is now compulsory in some ongoing trials22,23in
order to identify patients eligible for TKI treatment. Considering the large number of partner genes reported, screening for ABL-class fusions by RT-PCR analyses would be cumbersome, time-consuming,
costly, and—if a novel partner gene is involved—unsuccessful. Hence,
in clinical routine, most laboratories apply FISH analyses, with RNA sequencing increasingly also being used. We used FISH to ascertain ABL-class rearrangements in a series of B-other cases from a single center and here report their frequencies in such a cohort and also summarize the genetic and clinical features of BCP ALL cases with the rare SFPQ-ABL1 fusion reported to date.
2
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M A T E R I A L S A N D M E T H O D S
2.1
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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 fix-ative 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). Twenty-four patients (44%) had NCI standard risk (age 1-10 years and
white blood cell count <50× 109/L) whereas 31 (56%) had NCI high risk
(age≥ 10 years and/or white blood cell count ≥50 × 109/L). Age, sex,
and karyotypes of the cases are provided in Table S1.
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).
2.2
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FISH and RT-PCR
FISH analyses were performed using the following probes: ABL1 (ZytoLight SPEC ABL1 Dual Color Break Apart Probe, Z-2199-50, ZytoVision GmbH, Bremerhaven, Germany), ABL2 (ZytoLight SPEC ABL2 Dual Color Break Apart Prob, Z-2200-50, ZytoVision GmbH),
and PDGFRB (Vysis LSI PDGFRB Dual Color Break Apart
Rearrangement Probe, Abbott Molecular, Des Plaines, IL). The latter probe also covers the CSF1R gene, located in close proximity to the PDGFRB gene; thus, rearrangements of these two genes cannot be
distinguished using that probe.17In addition, the Vysis LSI BCR/ABL
Dual Color, Dual Fusion Translocation Probe (Abbott Molecular) was applied in one case with a low frequency of ABL1-rearranged cells (see below). The analyses were performed using a Zeiss Axioplan
2 microscope (Carl Zeiss AG, Oberkochen, Germany) and the Cyto-Vision software (Leica Biosystems, Nussloch, Germany). For each probe, 200 interphase cells/patient were analyzed. Based on analyses of normal bone marrow samples, the cut-off values (median + 3SD) for split signals were 1.3%, 0%, and 1.6% for the ABL1, ABL2, and CSF1R/PDGFRB probes, respectively.
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.10The
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).
3
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R E S U L T S A N D D I S C U S S I O N
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 ferent NCI risk cohorts or cytogenetic subgroups analyzed and/or dif-ferent methodologies used. However, our frequencies in B-other
cases are on par with previously published series.7,8,22,24-27
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 Color, Dual Fusion Translocation Probe (Abbott Molecular). Twenty-four of 211 interphase cells (11.4%) displayed three signals (one large and two smaller ones) of the ABL1 probe, confirming the presence of an ABL1 rearrangement. Unfortunately, no RNA was available for RNA sequencing and, hence, the partner gene could not be ascertained. Because this patient was diagnosed in the pre-TKI era (2001), no action could be taken based on these FISH results. The third case had a t(1;9)(p34;q34) that, with RT-PCR, was shown to fuse exon 9 of SFPQ with exon 4 of ABL1.
With the exception of the EBF1-PDGFRB and ETV6-ABL1 fusions, which have been reported in a relatively large number of BCP
ALLs,23,28most ABL-class rearrangements have been reported only in
single or a handful of cases. Thus, little is known about their associ-ated clinical features. For example, SFPQ-ABL1 has so far only been
reported in six BCP ALLs, including the present case (Table 1).10,29-31
Apart from being fused to ABL1 in BCP ALL, SFPQ is rearranged, most
often as the 50partner, with other genes in some human malignancies:
TFE3 in renal cell carcinomas and perivascular epithelioid cell
tumors,32,33ZFP36L1 and ZFP36L2 in pediatric T-cell ALL,34,35and
RLF in breast cancer.36The 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 hyper-leukocytosis. Unfortunately, detailed immunophenotypes of most published cases have either not been mentioned or only superficially described (Table 1) and hence no characteristic immunophenotypic features of SFPQ-ABL1-positive BCP ALL can be deduced from the limited data available. Also the data on genetic changes present in addition to the SFPQ-ABL1 fusion are scarce, mainly because most reported cases have only been analyzed by conventional chromosome
banding—in general, the t(1;9)(p34;q34) has been the sole change or
accompanied by only one or two cytogenetically identifiable abnor-malities. However, IKZF1 deletions were detected in two of the three cases where data on such deletions were available (refs. 30, 31 and present case; Table 1), which agrees with the frequent occurrence of
IKZF1 loss in Ph-like BCP ALL.3,6 For several ABL-class fusions, for
example ETV6-ABL1, NUP214-ABL1, RANBP2-ABL1, and
RCSD1-ABL2, there are in vitro, ex vivo, mouse, as well as clinical data
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 treat-ment was reported, only those receiving TKI and/or undergoing allo-geneic 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.
C O N F L I C T O F I N T E R E S T
The authors declare no conflict of interest.
D A T A A V A I L A B I L I T Y S T A T E M E N T
Data sharing is not applicable to this article as no new data were cre-ated or analyzed in this study.
O R C I D
Bertil Johansson https://orcid.org/0000-0001-8829-4813
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S U P P O R T I N G I N F O R M A T I O N
Additional supporting information may be found online in the Supporting Information section at the end of this article.
How to cite this article: Biloglav A, Olsson-Arvidsson L, Theander J, Behrendtz M, Castor A, Johansson B. SFPQ-ABL1-positive B-cell precursor acute lymphoblastic leukemias. Genes
Chromosomes Cancer. 2020;59:540–543.https://doi.org/10.
1002/gcc.22852
