PAX5 fusion genes are frequent in poor risk childhood acute lymphoblastic leukaemia and can be targeted with BIBF1120

Emerging Epigenetic and Posttranslational Mechanisms Controlling Resistance to Glucocorticoids in Acute Lymphoblastic Leukemia

“…For instance, recent work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth in competition with GCs, as described earlier. 39,149 This justifies efforts to sensitize leukemia cells to GC response with LCK inhibitors such as dasatinib, bosutinib, and nintedanib both in T-ALL and BCP-ALL, 39,79,146 as well as with dasatinib derivatives coupled to a proteolysis-targeting chimera approach against LCK. 172 The LCK inhibitor dasatinib in combination with mTORC1 inhibition induced potent T-ALL cell death through reducing MCL-1 protein expression.…”

“…76,77 LCK hyperactivation at diagnosis has been associated with T-ALL PPR status in ETP-ALL patients 39,78 as well as with PAX5 translocation-related poor prognosis in B cell precursor (BCP)-ALL subgroups. 79 NFAT family members have been widely described as crucial for many aspects of the immune response and for the maintenance of the T-ALL phenotype. 80,81 Physiologically, GCs can modulate intracellular Ca 2+ levels by inducing the expression of serum and GC-inducible kinase-1 (SGK1), which is involved in tumor growth and resistance to GC chemotherapy.…”

“…TCR signaling involves the downstream phosphorylation of the lymphocyte‐specific protein tyrosine kinase (LCK) that induces a sustained Ca 2+ influx via the plasma membrane Ca 2+ channel (CRAC) and the activation of calmodulin by Ca 2+ binding, which in turn activates the calcineurin phosphatase that dephosphorylates the nuclear factor of activated T‐cells (NFAT) TF family, allowing their import into the nucleus and a consequent initiation of transcriptional programs 76,77 . LCK hyperactivation at diagnosis has been associated with T‐ALL PPR status in ETP‐ALL patients 39,78 as well as with PAX5 translocation‐related poor prognosis in B cell precursor (BCP)‐ALL subgroups 79 . NFAT family members have been widely described as crucial for many aspects of the immune response and for the maintenance of the T‐ALL phenotype 80,81 .…”

Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia

“…GEP was analyzed by Affymetrix HG‐U133 Plus 2.0 arrays for the 64 DS‐ALL AIEOP patients (GEO accession number: GSE2000864). Each patient was classified according to the previously published diagnostic classifier (DC) based on the GEP; 15–17 a cohort of 289 childhood BCP‐ALL non‐DS cases at diagnosis enrolled in Italy in the AIEOP‐BFM ALL2000/R2006 protocols was also included (GEO accession numbers: GSE79547, GSE13164, GSE13159, and GSE13204) 18 . Details are given in the supplementary material.…”

“…[15][16][17] Most of the DS-ALL patients (46/64) were classified as Ph-like, 12 cases as ETV6::RUNX1 or ETV6::RUNX1-like (6/12 carried the t[12;21] translocation), 2 as TCF3::PBX1 (both positive for the t[1;19] translocation), and 4 as ALL with a hyperdiploid/hyperdiploid-like karyotype (all 4 cases had 48 chromosomes) (Figure 2A). The t-SNE analysis, using the top 1000 variable genes of both DS-ALL and no DS-ALL patients, showed that the Down syndrome patients were not characterized by a unique and peculiar expression profile, but shared features with the different BCP-ALL subgroups 18 (Suppl. Figure S2).…”