PAX5 deletion

PAX5 structural aberrations are common and important genetic events in B-ALL with various forms, including in- frame gene fusions, 3' deletion ( PAX5::ZCCHC7 ), and focal exon deletions. OGM combined with RNA-seq helps to decipher pathological PAX5 structural abnormalities. PAX5 structural abnormalities mostly occur in BCR::ABL1 - positive and BCR::ABL1 -like patients and are often associated with IK10.

We identified 196 pts with ND-ALL who had CGAT testing performed at diagnosis and received treatment at our center: 54 pts with available data comprised our initial discovery set (Table). CGAT among these pts disclosed large segmental CNAs frequently associated with ALL, such as gains of chromosome X, 1/1q, and 8q; and deletions of 7p, 9p, and 12p. Peak regions with CNAs were detected, which are regions with higher frequencies of aberrations compared with chromosomal segments on either side.

In conclusion, we present a boy with ALL carrying a de novo germline PAX5 exon 6 deletion leading to a truncated protein. Germline PAX5 deletions have not yet been described in ALL patients but since somatic PAX5 aberrations are common in ALL and germline PAX5 variants have been associated with ALL, we consider that this focal germline PAX5 deletion did contribute to leukaemia development in the boy.

Our study showed that PAX5 haploinsufficiency induced low T cell infiltration in TME using decreased chemokines.

The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al...PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT)...Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT...OS (A) and DFS (B). PONALFIL vs. ALL Ph08.

Our study showed that PAX5 haploinsufficiency induced CD8+ T cells dysfunction or exhaustion by high expression of TIM3, NR4A1 and BATF in the CD8+ T cells of TME.

Conclusion Despite it is a small cohort, the results confirm that the combination of conventional cytogenetic risk and CNV analysis allows a better classification of the biological risk of the disease. We can identify a group with a very good prognosis (CYT-GR and CNV-GR) with 4-years EFS of 100% and a group with higher probability of relapse (CYT-GR/IR and CNV-PR) with 4-years EFS of 38%.