The Current Genomic and Molecular Landscape of Philadelphia-like Acute Lymphoblastic Leukemia

Abstract

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) is a high-risk B-cell Acute Lymphoblastic Leukemia (B-ALL) characterized by a gene expression profile similar to Ph-positive B-ALL but lacking the BCR-ABL1 translocation. The molecular pathogenesis of Ph-like B-ALL is heterogenous and involves aberrant genomics, receptor overexpression, kinase fusions, and mutations leading to kinase signaling activation, leukemogenic cellular proliferation, and differentiation blockade. Testing for the Ph-like signature, once only a research technique, is now available to the clinical oncologist. The plethora of data pointing to poor outcomes for this ALL subset has triggered investigations into the role of targeted therapies, predominantly involving tyrosine kinase inhibitors that are showing promising results.

Keywords: CRLF2; PI3K/AKT/mTOR; acute lymphoblastic leukemia; targeted therapy.

Figure 1

Schematic representation of the CRLF2-receptor complex.

Figure 2

Genomic alterations in adults with Ph-like acute lymphoblastic leukemia (ALL). Pie chart constructed with data from Roberts et al. [67].

Figure 3

Genomic alterations in children with Ph-like ALL. Pie chart constructed with data from Roberts et al. and Reshmi et al. [14,32].

Figure 4

Proposed testing algorithm for Ph-like ALL in the clinical setting. MLL: Mixed Lineage Leukemia; FISH: fluorescent in situ hybridization; PCR: polymerase chain reaction; LDA: low density array. *Other aberrations include—ABL1, ABL2, CRLF2, JAK2, EPOR, PDGFRB, and CSF1R.