<i>SSBP2-CSF1R</i> is a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome

Schwab, Claire; Roberts, Kathryn G.; Boer, Judith M.; Göhring, Gudrun; Steinemann, Doris; Vora, Ajay; Macartney, Christine; Hough, Rachael; Thorn, Zoe; Dillon, Richard; Escherich, Gabriele; Cazzaniga, Giovanni; Schlegelberger, Brigitte; Loh, Mignon; Boer, Monique L. Den; Moorman, Anthony V.; Harrison, Christine J.

doi:10.1182/blood.2020008536

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…Due to the small number of patients, we were unable to examine outcome for each fusion individually. However, we have previously shown that the EBF1–PDGFRB fusion is associated with high levels of MRD and high RR, 26 whereas SSBP2–CSF1R fusions relate to a more variable outcome 38 . A recent collaborative study has shown that patients with PDGFRB and ABL2 fusions have an inferior five‐year EFS compared to those with CSF1R and ABL1 fusions 39 .…”

Section: Discussionmentioning

confidence: 95%

“…However, we have previously shown that the EBF1-PDGFRB fusion is associated with high levels of MRD and high RR, 26 whereas SSBP2-CSF1R fusions relate to a more variable outcome. 38 A recent collaborative study has shown that patients with PDGFRB and ABL2 fusions have an inferior five-year EFS compared to those with CSF1R and ABL1 fusions. 39 However, in the context of childhood ALL, ABLclass fusions overall have been associated with an unfavourable outcome.…”

Section: Discussionmentioning

confidence: 99%

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Genetic characterisation of childhood B‐other‐acute lymphoblastic leukaemia in UK patients by fluorescence in situ hybridisation and Multiplex Ligation‐dependent Probe Amplification

et al. 2021

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While next-generation sequencing technologies provide excellent strategies to screen for newly defined genetic abnormalities of prognostic or therapeutic significance in patients with B-other-acute lymphoblastic leukaemia (ALL), they are not widely available. We used a dual screening approach, incorporating fluorescence in situ hybridisation (FISH) and Multiplex Ligation-dependent Probe Amplification (MLPA), to establish the frequency and long-term outcome of a representative cohort of specific subgroups of B-other-ALL recruited to the childhood ALL trial, UKALL2003. We focussed on abnormalities of known prognostic significance, including ABL-class fusions and ERG deletions, as a surrogate marker for DUX4rearranged ALL. ABL-class fusions accounted for ~4% of B-other-ALL and were associated with high levels of minimal residual disease (MRD; 14/23 with MRD >5%) and a high relapse rate (55Á7%) following treatment without tyrosine kinase inhibitor (TKI), confirming the importance of prospective screening with a view to incorporating TKI into therapy. Patients with deletions of ERG (~10% of B-other-ALL) had a 10-year event-free-survival of 97Á2%, validating previous reports of their excellent outcome. Rearrangements of ZNF384, MEF2D and NUTM1 were observed at low frequencies. Here, we estimate that approximately one third of B-other-ALL patients can be reliably classified into one of the known genetic subgroups using our dual screening method. This approach is rapid, accurate and readily incorporated into routine testing.

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Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Genetic characterisation of childhood B‐other‐acute lymphoblastic leukaemia in UK patients by fluorescence in situ hybridisation and Multiplex Ligation‐dependent Probe Amplification

et al. 2021

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“…Previously described gene fusions and SNVs represent only a portion of clinically relevant genomic alterations affecting ALL patients, limiting the applicability of RaScALL. To enable detection of a broader range of genomic alterations, we performed a literature search identifying an additional 46 gene fusions and 26 SNVs reported in multiple ALL patients and associated with functional effects [5,8,[50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67]. Targets for these variants, and any alterations undetected in the study cohort, were generated using RaScALL's custom target generation tool (see Materials and Methods), resulting in an expanded target set representing 75 distinct gene fusions and sequence variants affecting 14 cancer-related genes (S5 Table ).…”

Section: Rascall Accurately Identifies Subtype Defining Alterations I...mentioning

confidence: 99%

RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL)

Rehn

Mayoh²,

Heatley³

et al. 2022

PLoS Genet

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RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, integrating RNA-seq in a clinical setting requires rapid detection and accurate reporting of clinically relevant alterations. Here we present RaScALL, an implementation of the k-mer based variant detection tool km, capable of identifying more than 100 prognostically significant lesions observed in ALL, including gene fusions, single nucleotide variants and focal gene deletions. We compared genomic alterations detected by RaScALL and those reported by alignment-based de novo variant detection tools in a study cohort of 180 Australian patient samples. Results were validated using 100 patient samples from a published North American cohort. RaScALL demonstrated a high degree of accuracy for reporting subtype defining genomic alterations. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% of reported cases in the study cohort (n = 164) and 95% of samples (n = 63) in the validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n = 12) and IKZF1 p.N159Y (n = 4). Intragenic IKZF1 deletions resulting in aberrant transcript isoforms were also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches. The application of RaScALL enables rapid identification and reporting of previously identified genomic alterations of known clinical relevance.

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“…The prevalence of these rearrangements is 17% in children, 9% in adolescents, 10% young adults and 9% older adults [ 4 , 12 , 14 , 15 ]. Patients with ABL-class fusions respond poorly to chemotherapy regimens, and the EBF1-PDGFRB fusion in particular is associated with induction failure [ 42 , 43 , 44 ]. All fusions preserve the tyrosine kinase of the ABL-class gene and promote constitutive kinase signaling that confers the ability to survive and grow independently of cytokine in vitro [ 45 ].…”

Section: Genomic Features Of Ph-like Allmentioning

confidence: 99%

Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia

Iacobucci

Roberts

2021

Genes

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Philadelphia-like (Ph-like) acute lymphoblastic leukemia (ALL) is a subgroup of B-cell precursor ALL which by gene expression analysis clusters with Philadelphia-positive ALL although lacking the pathognomonic BCR-ABL1 oncoprotein. Its prevalence increases with age and similar to BCR-ABL1-positive ALL, Ph-like ALL is characterized by IKZF1 or other B-lymphoid transcription factor gene deletions and by poor outcome to conventional therapeutic approaches. Genetic alterations are highly heterogenous across patients and include gene fusions, sequence mutations, DNA copy number changes and cryptic rearrangements. These lesions drive constitutively active cytokine receptor and kinase signaling pathways which deregulate ABL1 or JAK signaling and more rarely other kinase-driven pathways. The presence of activated kinase alterations and cytokine receptors has led to the incorporation of targeted therapy to the chemotherapy backbone which has improved treatment outcome for this high-risk subtype. More recently, retrospective studies have shown the efficacy of immunotherapies including both antibody drug-conjugates and chimeric antigen receptor T cell therapy and as they are not dependent on a specific genetic alteration, it is likely their use will increase in prospective clinical trials. This review summarizes the genomic landscape, clinical features, diagnostic assays, and novel therapeutic approaches for patients with Ph-like ALL.

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SSBP2-CSF1R is a recurrent fusion in B-lineage acute lymphoblastic leukemia with diverse genetic presentation and variable outcome

Cited by 6 publications

References 12 publications

Genetic characterisation of childhood B‐other‐acute lymphoblastic leukaemia in UK patients by fluorescence in situ hybridisation and Multiplex Ligation‐dependent Probe Amplification

Genetic characterisation of childhood B‐other‐acute lymphoblastic leukaemia in UK patients by fluorescence in situ hybridisation and Multiplex Ligation‐dependent Probe Amplification

RaScALL: Rapid (Ra) screening (Sc) of RNA-seq data for prognostically significant genomic alterations in acute lymphoblastic leukaemia (ALL)

Genetic Alterations and Therapeutic Targeting of Philadelphia-Like Acute Lymphoblastic Leukemia

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