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Review
. 2016 May 27:35:48.
doi: 10.1186/s40880-016-0108-0.

The Philadelphia chromosome in leukemogenesis

Zhi-Jie Kang  1   2 , Yu-Fei Liu  1   2 , Ling-Zhi Xu  3 , Zi-Jie Long  4 , Dan Huang  1 , Ya Yang  1   2 , Bing Liu  1   2 , Jiu-Xing Feng  1   2 , Yu-Jia Pan  1   2 , Jin-Song Yan  5 , Quentin Liu  6   7
Affiliations
Review

The Philadelphia chromosome in leukemogenesis

Zhi-Jie Kang et al. Chin J Cancer. .

Abstract

The truncated chromosome 22 that results from the reciprocal translocation t(9;22)(q34;q11) is known as the Philadelphia chromosome (Ph) and is a hallmark of chronic myeloid leukemia (CML). In leukemia cells, Ph not only impairs the physiological signaling pathways but also disrupts genomic stability. This aberrant fusion gene encodes the breakpoint cluster region-proto-oncogene tyrosine-protein kinase (BCR-ABL1) oncogenic protein with persistently enhanced tyrosine kinase activity. The kinase activity is responsible for maintaining proliferation, inhibiting differentiation, and conferring resistance to cell death. During the progression of CML from the chronic phase to the accelerated phase and then to the blast phase, the expression patterns of different BCR-ABL1 transcripts vary. Each BCR-ABL1 transcript is present in a distinct leukemia phenotype, which predicts both response to therapy and clinical outcome. Besides CML, the Ph is found in acute lymphoblastic leukemia, acute myeloid leukemia, and mixed-phenotype acute leukemia. Here, we provide an overview of the clinical presentation and cellular biology of different phenotypes of Ph-positive leukemia and highlight key findings regarding leukemogenesis.

Keywords: BCR-ABL1; Chronic myeloid leukemia; Philadelphia chromosome; Signaling pathway; Translocations.

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Figures

Fig. 1
Fig. 1
The structure of the breakpoint cluster region (BCR)-proto-oncogene tyrosine-protein kinase (ABL1) gene and protein. a The BCR-ABL1 fusion gene consists of the 5′ end of the BCR gene located at 22q11 and the 3′ end of the ABL1 gene located at 9q34. The breakpoints of the translocation usually involve the intron 13 or 14 of BCR, named major breakpoint (M-BCR), intron 1 of BCR, named minor breakpoint (m-BCR), and exon 19 of BCR, named μ breakpoint (μ-BCR). For ABL1, the breakpoint always involves the region between exons 1b and 2. b The BCR-ABL1 protein contains the Ser/Thr kinase domain and the Rho/GEF domain of BCR and the src homology (SH) domains, nuclear localization signal (NLS), and actin-binding domains from ABL1. The SH1 kinase domain is the target of imatinib. The different breakpoints that generate the p230, p210, and p190 isoforms are shown
Fig. 2
Fig. 2
Main pathways regulated by the BCR-ABL1 protein. The downstream pathways regulated by BCR-ABL1 protein associated with cell survival, cell proliferation, cell cycle, cell differentiation, apoptosis, and the microenvironment of leukemia stem cells. Dark violet shapes indicate the kinase; lavender pink shapes indicate the proven oncoprotein; blue shapes indicate the proven tumor suppressor protein; and other color shapes indicate the proteins existing in normal cells. Red solid lines indicate inhibiting; green solid lines indicate activating. Blue dotted lines indicate that the results need further confirmation. Black dotted lines indicate the functions associated with the signaling pathway. JAK2 janus kinase 2, STAT5 signal transducers and activators of transcription 5, BCR-XL B-cell lymphoma-extra-large, CRKL Crk-like protein, PI3 K phosphatidylinositol 3-kinase, AKT protein kinase B, MDM2 mouse double minute 2 homolog, TP53 tumor protein p53, p21WAF-1/CIP-1 cytosolic cyclin-dependent kinase inhibitor p21, SKP2I S-phase kinase-associated protein 2 inhibitor, NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells, IKKβ IKβ kinase, C/EBPα CCAAT/enhancer-binding protein α, GATA2 GATA binding protein 2, GRB2 the adaptor protein growth factor receptor-bound protein 2, SOS son of sevenless, MEK mitogen-activated protein kinase kinase, ERK extracellular signal-regulated kinases, hnRNP-E2 poly(rC)-binding protein E2, FOXO3a forkhead box O3, TRAIL TNF-related apoptosis-inducing ligand
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