Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor

  title={Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large‐cell lymphoma and inflammatory myofibroblastic tumor},
  author={Jan Cools and Iwona Wlodarska and Riet Somers and Nicole Mentens and Florence Pedeutour and Brigitte Maes and Chris de Wolf‐Peeters and Patrick Pauwels and Anne M. Hagemeijer and Peter Marynen},
ALK‐positive anaplastic large‐cell lymphoma (ALCL) has been recognized as a distinct type of lymphoma in the heterogeneous group of T/Null‐ALCL. While most of the ALK‐positive ALCL (ALKomas) are characterized by the presence of the NPM‐ALK fusion protein, the product of the t(2;5)(p23;q35), 10–20% of ALKomas contain variant ALK fusions, including ATIC‐ALK, TFG‐ALK, CLTC‐ALK (previously designated CLTCL‐ALK), TMP3‐ALK, and MSN‐ALK. TMP3‐ALK and TMP4‐ALK fusions also have been detected in… 
Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma with the variant RNF213-, ATIC- and TPM3-ALK fusions is characterized by copy number gain of the rearranged ALK gene
Lymphomas driven by the variant ATIC-ALK fusion (and likely by RNF213-ALK and TPM3-ALK), but not the classic NPM1-ALK, require an increased dosage of the ALK hybrid gene to compensate for the relatively low and insufficient expression and signaling properties of the chimeric gene.
Genomic profiling reveals different genetic aberrations in systemic ALK‐positive and ALK‐negative anaplastic large cell lymphomas
ALK‐positive and negative ALCL have different secondary genomic aberrations, suggesting they correspond to different genetic entities.
Development of anaplastic lymphoma kinase (ALK) small‐molecule inhibitors for cancer therapy
A succinct summary of normal ALK biology, the confirmed and putative roles of ALK fusions and the full‐length ALK receptor in the development of human cancers, and efforts to target ALK using small‐molecule kinase inhibitors is provided.
Molecular investigation of ALK‐rearranged epithelioid fibrous histiocytomas identifies CLTC as a novel fusion partner and evidence of fusion‐independent transcription activation
The present study examines a cohort of ALK‐immunoreactive EFH cases to further characterize gene fusion partners and reports the first report of CLTC as a fusion partner in EFH, indicating a fusion independent transcription mechanism as seen in other tumors.
Consultations in Molecular Diagnostics 5-( RACE ) Identification of Rare ALK Fusion Partner in Anaplastic Large Cell Lymphoma
The 5 -rapid amplification of cDNA ends (RACE) technique revealed a fusion between tropomyosin 3 (TPM3) and the ALK genes that raises the possibility that other yet unidentified genes that partner with ALK may be involved in the pathogenesis of these tumors.
Pulmonary Inflammatory Myofibroblastic Tumor Expressing a Novel Fusion, PPFIBP1–ALK: Reappraisal of Anti-ALK Immunohistochemistry as a Tool for Novel ALK Fusion Identification
The current ALK positivity rate in IMT should be reassessed with a more highly sensitive method such as iAEP to accurately identify those patients who might benefit from ALK-inhibitor therapies, and will broaden the potential value of immunohistochemistry.
ALK activation by the CLTC-ALK fusion is a recurrent event in large B-cell lymphoma.
We present 3 cases of large B-cell lymphoma (LBCL) with a granular cytoplasmic staining for anaplastic lymphoma kinase (ALK). All of the cases showed striking similarities in morphology and
ALK-positive diffuse large B-cell lymphoma is associated with Clathrin-ALK rearrangements: report of 6 cases.
It is clearly demonstrated that most cases of ALK+ DLBCL share the same mechanism of deregulated ALK expression, and the presence of CLTC-ALK fusions in these tumors is demonstrated and the list of diseases associated with this genetic abnormality is extended to include classical T-cell or null ALCL, ALK +DLBCL, and inflammatory myofibroblastic tumors.
Prognostic significance of NPM-ALK fusion transcript overexpression in ALK-positive anaplastic large-cell lymphoma
Overexpression of the NPM-ALK fusion transcript may be associated with a poor prognosis of the patients with ALK+ anaplastic large-cell lymphomas, and RT-PCR and 5′ RACE assays developed here may be useful for identification of known and unknown gene partners fused to the ALK gene.
ALK-positive large B-cell lymphomas with cryptic SEC31A-ALK and NPM1-ALK fusions
It is shown that the ALK inhibitor TAE-684 reduces cell proliferation and kinase activity of SEC31A-ALK and its downstream effectors ERK1/2, AKT, STAT3 and STAT5, and that this variant fusion transforms IL3-dependent Ba/F3 cells to growth factor independence.


Molecular Characterization of a New ALK Translocation Involving Moesin (MSN-ALK) in Anaplastic Large Cell Lymphoma
The moesin (MSN) gene at Xq11–12 is identified as a new partner of ALK in a case of ALCL which exhibited a distinctive membrane-restricted pattern of ALC labeling and indicates that MSN may act as an alternative fusion partner for activation of ALk in ALCL and provide further evidence that oncogenic activation ofALK may occur at different intracellular locations.
The monoclonal antibody ALK1 identifies a distinct morphological subtype of anaplastic large cell lymphoma associated with 2p23/ALK rearrangements.
Investigation for ALK expression cases diagnosed as ALCL as well as lympho-proliferative disorders possessing overlapping features with ALCL allows the identification of a distinct subgroup within the ALCL of T or null phenotype that is associated with 2p23 abnormalities and lacks the marked histological pleomorphism described in ALCL.
The cryptic inv(2)(p23q35) defines a new molecular genetic subtype of ALK-positive anaplastic large-cell lymphoma.
It is demonstrated that the inv(2)(p23q35), a variant of the t(2;5)( p23;q 35), is a recurrent chromosomal abnormality in ALK-positive ALCL, the further characterization of which should provide new insight into the pathogenesis of these lymphomas.
The NPM-ALK and the ATIC-ALK fusion genes can be detected in non-neoplastic cells.
ALK expression defines a distinct group of T/null lymphomas ("ALK lymphomas") with a wide morphological spectrum.
Further demonstration of the diversity of chromosomal changes involving 2p23 in ALK-positive lymphoma: 2 cases expressing ALK kinase fused to CLTCL (clathrin chain polypeptide-like).
2 lymphomas with an unusual finely granular cytoplasmic ALK staining pattern are reported, clearly different from the pattern observed in ALK-positive lymphomas carrying NPM-ALK or its variants and further illustrate the diversity of fusion partners for the ALK gene.
CD30(+) anaplastic large cell lymphoma: a review of its histopathologic, genetic, and clinical features.
Recent immunohistologic studies suggest that ALCLs Hodgkin-like represent either cases of tumor cell-rich classic Hodgkin disease or (less commonly) ALK(+) ALCL orALK(-) ALCL, both of which have an unfavorable prognosis.
TRK-fused gene (TFG) is a new partner of ALK in anaplastic large cell lymphoma producing two structurally different TFG-ALK translocations.
TFG can provide an alternative to NPM as a fusion partner responsible for activation of the ALK and the pathogenesis of ALCL, showing that the new cloned cDNA sequences are translated into chimeric proteins with functional activity.
Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.
Results indicate that reliable immunostaining of routine biopsy material for NPM-ALK and ALK proteins is feasible and of diagnostic importance, especially because t(2;5)+ ALCL cases have a good prognosis with appropriate treatment.