CRLF2 blocking peptide

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a recently described subtype of B-cell precursor ALL with a gene expression profile similar to Ph-positive ALL and a high frequency of IKZF1 alterations. The prevalence of Ph-like ALL increases with age, ranging from 10-15% of children to over 25% of young adults with ALL. It occurs more frequently in males and is associated with adverse clinical features including elevated minimal residual disease levels and poor survival in both children and adults. The genomic landscape of Ph-like ALL is characterized by a diverse range of genetic alterations that dysregulate cytokine receptor and kinase signaling pathways, including rearrangement of CRLF2 and other tyrosine kinases (predominantly ABL-class and Janus kinases). Compelling preclinical data suggest patients harboring ABL-class rearrangements are candidates for ABL1-inhibitors, whilst alterations activating the JAK-STAT pathway may be amenable to treatment with JAK inhibitors. The success of combinatorial treatment of tyrosine kinase inhibitors with chemotherapy in Ph-positive ALL provides a framework for testing this approach in Ph-like ALL Ongoing prospective studies will determine if incorporation of targeted therapy with intensive chemotherapy regimens will improve the outcome of patients with Ph-like ALL. (C) 2017 Elsevier Ltd. All rights reserved.

Further improvement of outcome in childhood acute lymphoblastic leukemia could be achieved by identifying additional high-risk patients who may benefit from intensified treatment. We earlier identified PTPRC (CD45) gene expression as a potential new stratification marker and now analyzed the prognostic relevance of CD45 protein expression. CD45 was measured by flow cytometry in 1065 patients treated according to the ALL-BFM-2000 protocol. The 75th percentile was used as cut-off to distinguish a CD45-high from a CD45-low group. As mean CD45 expression was significantly higher in T-cell acute lymphoblastic leukemia than in B-cell-precursor acute lymphoblastic leukemia (P<0.0001), the analysis was performed separately in both groups. In B-cell-precursor acute lymphoblastic leukemia we observed a significant association of a high CD45 expression with older age, high initial white blood cell count, ETV6/RUNX1 negativity, absence of high hyperdiploidy (P<0.0001), MLL/AF4 positivity (P=0.002), BCR/ABL1 positivity (P=0.007), prednisone poor response (P=0.002) and minimal residual disease (P<0.0001). In T-cell acute lymphoblastic leukemia we observed a significant association with initial white blood cell count (P=0.0003), prednisone poor response (P=0.01), and minimal residual disease (P=0.02). Compared to CD45-low patients, CD45-high patients had a lower event-free survival rate (B-cell-precursor acute lymphoblastic leukemia: 72 +/- 3% versus 86 +/- 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 60 +/- 8% versus 78 +/- 4%, P=0.02), which was mainly attributable to a higher cumulative relapse incidence (B-cell-precursor acute lymphoblastic leukemia: 22 +/- 3% versus 11 +/- 1%, P<0.0001; T-cell acute lymphoblastic leukemia: 31 +/- 8% versus 11 +/- 3%, P=0.003) and kept its significance in multivariate analysis considering sex, age, initial white blood cell count, and minimal residual disease in B-cell-precursor-and T-cell acute lymphoblastic leukemia, and additionally presence of ETV6/RUNX1, MLL/AF4 and BCR/ABL1 rearrangements in B-cell-precursor acute lymphoblastic leukemia (P=0.002 and P=0.025, respectively). Consideration of CD45 expression may serve as an additional stratification tool in BFM-based protocols.