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Review
. 2017 Nov 9;130(19):2064-2072.
doi: 10.1182/blood-2017-06-743252. Epub 2017 Oct 2.

Philadelphia chromosome-like acute lymphoblastic leukemia

Affiliations
Review

Philadelphia chromosome-like acute lymphoblastic leukemia

Sarah K Tasian et al. Blood. .

Abstract

Philadelphia chromosome (Ph)-like acute lymphoblastic leukemia (ALL), also referred to as BCR-ABL1-like ALL, is a high-risk subset with a gene expression profile that shares significant overlap with that of Ph-positive (Ph+) ALL and is suggestive of activated kinase signaling. Although Ph+ ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1 and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases, including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcomes, and genetic risk factors. Preclinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high-risk ALL subset.

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Figures

Figure 1.
Figure 1.
Incidence of Ph-like genetic alterations in children and adolescents and adults with B-lymphoblastic leukemia (B-ALL). Data are adapted from Reshmi et al (n = 284 patients) and Roberts et al (n = 194 patients). AYA, adolescents and young adults.
Figure 2.
Figure 2.
CRLF2 rearrangements in Ph-like ALL. (A) Interstitial deletion of the pseudoautosomal region (PAR1) of chromosomes X or Y places CRLF2 under control of the noncoding P2RY8 or CSF2RA promoters (dotted bar) to drive fusion transcript expression (thin arrows) and protein (thick arrows) translation (thin arrows). (B) IGH-CRLF2 fusion results from t(X;14) or t(Y;14). IGH is noncoding in the fusions (dotted bar). Both rearrangements result in CRLF2 overexpression and increased CRLF2 protein expression detectable by flow cytometry. (C) Rare CRLF2 point mutations lead to CRLF2 homodimerization and constitutive kinase signaling.
Figure 3.
Figure 3.
Schema of activated kinase signaling in Ph-like ALL. Kinase fusions and other alterations in Ph-like ALL activate oncogenic signal transduction and may be targetable by specific kinase inhibitors and other therapeutic agents.
Figure 4.
Figure 4.
ABL-class kinase fusions and other JAK pathway alterations in Ph-like ALL. (A) JAK2 fusions are caused by translocations or interstitial deletions involving various 5′ fusion partners that lead to constitutive activation of the JAK2 3′ gene tyrosine kinase domain (striped bars). (B) Rearrangements of the EPOR gene with accompanying frameshift or stop codon mutations lead to overexpression of a truncated EPOR protein that lacks negative regulatory tyrosine (Y) residues (patterned box). Other JAK/STAT alterations (TYK2, IL7R, and TSLP) are caused by (C) translocations or (D) insertions, deletions, or missense mutations (black bar). (E) ABL-class (eg, ABL1, ABL2, CSF1R, and PDGFRB) kinase fusions occur via similar mechanisms as in panel A.
Figure 5.
Figure 5.
Current Ph-like ALL genetic testing algorithm used by the Children's Oncology Group. Diagnostic leukemia cells from children with high risk B-ALL are first screened for the Ph-like ALL gene expression signature using an 8-gene low density microarray (LDA) that includes CRLF2 as one of the 8 assessed genes. Specimens with the Ph-like ALL signature that lack BCR-ABL1 fusion (Ph+ ALL) undergo additional genetic testing. Those with high CRLF2 expression are assessed for P2RY8-CRLF2 and IGH-CRLF2 rearrangements by RT-PCR and FISH, respectively, and for JAK1, JAK2 and IL7R mutations by PCR. Ph-like ALL specimens without CRLF2 overexpression undergo multiplex RT-PCR fusion testing to detect ABL-class, JAK2, and EPOR rearrangements. Not all Ph-like fusions will be detected by this algorithm. Complete assessment may require alternative assays for identification, such as RNA-sequencing or unbiased fusion testing capable of identifying new 5′ partners. HR B-ALL, high-risk B-ALL.

References

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