P2RY8-CRLF2 fusion

Furthermore, CRLF2_H/IKZF1del(+) patients had significantly lower CR, RFS, and OS rates and tended to have lower RFS and OS rates than others in the whole cohort and B-other patients, respectively. Therefore, coexistence of CRLF2_H and IKZF1del at diagnosis predicts poor response and outcome in adult Ph-negative BCP-ALL.

Here, we retrospectively studied outcomes of adult patients (pts) with r/r B-cell ALL who completed at least one cycle of a novel salvage therapy [blinatumomab (blina), inotuzumab (INO), or CD19CAR T cells (CAR)] at City of Hope from 2012 to 2022 and had post treatment disease assessment. Prior novel therapies did not adversely impact response to subsequent novel therapies. Therefore, the early introduction of novel therapies in pts with Ph-like ALL is of great interest and could potentially lead to improvement in frontline therapy outcomes in this high-risk entity.

Furthermore, we identify HMGN1H cells favour PAR1 deletion and the subsequent formation of the P2RY8-CRLF2 gene fusion after DSB and increase cell signalling pathways. Understanding the role of HMGN1 in DS-ALL patients has the potential to lead to novel therapeutic interventions in this high-risk group of patients with poor efficacious therapeutic options.

Cas9/gRNAs were transduced into Jurkat cells ± HMGN1 overexpression, activated with doxycycline and stained with TSLPR (CRLF2/IL-7Rα dimer) for single cell sort and clonal expansion...Using CRISPR/Cas9 in an in vitro model, we demonstrate that enforced high expression of HMGN1 alters DSB repair mechanism, favoring PAR1 deletion and the subsequent formation of the P2RY8-CRLF2 gene fusion, with attendant higher expression of STAT5 target genes. Understanding the role of HMGN1 in the disproportionate number of DS-ALL patients who are diagnosed with CRLF2r has the potential to lead to novel therapeutic interventions, in this high-risk group of patients where efficacious therapeutic options are currently poor.

Clinical molecular testing in our patients revealed gene alterations that provide refinement of diagnosis, prognosis, and risk stratification allowing the use of clinically actionable therapeutic targets in some cases. It also contributes toward a useful data set for further analysis and impactful targeted management. Longer-term follow-up incorporating therapy and outcomes information would be valuable.

The CRLF2 abnormality is found in 30-60% of DS-ALL cases. In the future, treatment of CRLF2, targeting JAKs downstream of CRLF2, and administration of blinatumomab or CAR-T therapy will be incorporated into DS-ALL treatment.

He relapsed three years later off treatment and was refractory to both salvage chemotherapy and blinatumomab...In a 3-day cell death assay, only P2RY8-CRLF2 + NF1 fs demonstrated sensitivity to trametinib (LD 50 P2RY8-CRLF2 = >6.4 µM, NF1 fs = >6.4 µM, P2RY8-CRLF2 + NF1 fs =1.7µM; p 16 µM, NF1 fs = >16 µM, P2RY8-CRLF2 + NF1 fs = 8.3 µM; p < 0.0001) (Figure 2)...An understanding of the genomic complexities that lead to relapse may also inform personalized treatment strategies. While this patient subsequently achieved remission with inotuzomab and underwent successful stem cell transplantation, the sensitivity to MEK inhibitors is an exciting development for neurofibromatosis patients with ALL.

We report a low overall frequency of ABL-class and JAK-STAT fusions and the absence of P2RY8-CRLF2 gene fusion in the Lithuanian BCR-ABL1 negative B-ALL cohort. Future (larger) studies are warranted to confirm an inferior event-free survival of ABL-class/JAK-STAT fusion-positive adult patients in MRD-directed protocols.

A marker phosphorylation signature was identified in BCR-ABL1 and TCF3-PBX1 patients. To obtain useful information for the assessment of treatment in B-ALL patients with recurrent gene fusions, we suggest that they should be evaluated at diagnosis for CRLF2 gene abnormalities and dominant-negative IKZF1 isoforms, in addition to the analyses of activation and inhibition of signaling pathways.

Seventy-five of these gene variants have not yet been described in B-cell precursor ALL to date. This study widens existing knowledge of the BCR-ABL1-like and B-other ALL genomic landscape in the adult population, supports previous findings, and identifies a number of novel gene variants.

In our cohort, the prevalence of previously reported relapse-specific mutation is relatively low, which may be caused by detection method and different ethnicity. Our novel cell line is useful staff for investigation to identify the role of DNA mismatch repair pathway in BCP-ALL leukemogenesis.

Development of successful treatment strategies to decrease relapse and to improve survival remains a major therapeutic gap for NCI HR CRLF2+ ALL patients. Current clinical trials are studying the potential efficacy of kinase inhibitor addition to chemotherapy for children, adolescents, and adults with HR Ph-like ALL harboring CRLF2 rearrangements/other JAK pathway alterations or ABL class kinase fusions (NCT0240717, NCT02723994, NCT02883049, NCT03571321).