| Entity | Anaplasic large cell lymphoma (ALCL) with t(2;5)(p23;q35) --> NPM1-ALK |
| Disease | ALCL are high grade non Hodgkin lymphomas; ALK+ ALCL are ALCL where ALK is involved in a fusion gene; ALK+ ALCL represent 50 to 60 % of ALCL cases (they are CD30+, ALK+;); 70 to 80% of ALK+ ALCL cases bear a t(2;5); the remaining ALK+ ALCL cases bear variant translocations described below and are called "cytoplasmic ALK+" cases, of which is the t(1;2) TPM3/ALK, found in 20% of ALK+ ALCL. |
| Prognosis | althouth presenting as a high grade tumour, a 80% five yr survival is associated with this anomaly |
| Cytogenetics | additional anomalies and complex karyotypes are most often found |
| Hybrid/Mutated Gene | 5' NPM1-3' ALK on the der(5) |
| Abnormal Protein | 680 amino acids, 80 kDa; N-term 116 amino acids from NPM1 fused to the 562 C-term aminoacids of ALK (i.e. composed of the oligomerization domain and the metal binding site of NPM1, and the entire cytoplasmic portion of ALK); no apparent expression of the ALK/NPM1 counterpart. Characteristic localisation both in the cytoplasm and in the nucleus, due to heterooligomerization of NPM-ALK and normal NPM whereas the normal NPM protein is confined to the nucleus; constitutive activation of the catalytic domain of ALK. |
| Oncogenesis | via the kinase function activated by oligomerization of NPM1-ALK mediated by the NPM1 part |
| | |
| Entity | Cytoplasmic ALK+ anaplasic large cell lymphoma |
| Prognosis | present a favourable prognosis comparable to the one found in t(2;5) ALK+ ALCL. |
| Cytogenetics | Either <t(X;2)(q11;p23), t(1;2)(q25;p23), inv(2)(p23q35), t(2;3)(p23;q21), t(2;17)(p23;q23), t(2;17)(p23;q25) or t(2;22)(p23;q11.2); hidden translocation is frequently found. |
| Hybrid/Mutated Gene | 5' MSN, TPM3, ATIC TFG, CLTC, ALO17 or MYH9 - 3' ALK |
| Abnormal Protein | N-term amino acids from the partner gene fused to the 562 C-term amino acids (in the great majority of cases) from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); cytoplasmic/membraneous localisation only. |
| Oncogenesis | the partner gene seems to provoke the dimerization of the fused-ALK, which should lead to constitutive autophosphorylation and activation of the ALK tyrosine kinase, as for NPM1-ALK (see t(2;5)(p23;q35) ). |
| | |
| Entity | Inflammatory myofibroblastic tumours with 2p23 rearrangements |
| Disease | rare soft tissue tumour found in children and young adults about one third to half of inflammatory myofibroblastic tumour cases present with a 2p23 rearrangement involving ALK. |
| Prognosis | good prognosis |
| Cytogenetics | t(1;2)(q25;p23), t(2;2)(p23;q13), t(2;11)(p23;p15), t(2;17)(p23;q23) , or t(2;19)(p23;p13.1) so far |
| Hybrid/Mutated Gene | 5' TPM3 in the t(1;2), RANBP2 in the t(2;2), CARS in the t(2;11), 5' CLTC in the t(2;17), or 5' TPM4 in the t(2;19)- 3' ALK |
| Abnormal Protein | N-term amino acids from the partner gene fused to the 562 C-term amino acids from ALK (i.e. the entire cytoplasmic portion of ALK with the tyrosine kinase domain); homodimerization of the fusion protein is known or suspected. |
| Oncogenesis | fused-ALK is contitutively activated |
| | |
| Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin's lymphoma. |
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| PMID 8122112 |
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| Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system. |
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| PMID 9053841 |
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| ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK) |
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| PMID 9174053 |
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| PMID 9121481 |
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| PMID 10216106 |
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| PMID 10934142 |
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| ATIC-ALK: A novel variant ALK gene fusion in anaplastic large cell lymphoma resulting from the recurrent cryptic chromosomal inversion, inv(2)(p23q35). |
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| PMID 10702393 |
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| Inv(2)(p23q35) in anaplastic large-cell lymphoma induces constitutive anaplastic lymphoma kinase (ALK) tyrosine kinase activation by fusion to ATIC, an enzyme involved in purine nucleotide biosynthesis. |
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| PMID 10706887 |
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| PMID 11090048 |
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| 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). |
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| Blood. 2000 ; 95 (10) : 3204-3207. |
| PMID 10807789 |
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| Pathobiology of NPM-ALK and variant fusion genes in anaplastic large cell lymphoma and other lymphomas. |
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| Fusion of the ALK gene to the clathrin heavy chain gene, CLTC, in inflammatory myofibroblastic tumor. |
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| The American journal of pathology. 2001 ; 159 (2) : 411-415. |
| PMID 11485898 |
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| Molecular characterization of a new ALK translocation involving moesin (MSN-ALK) in anaplastic large cell lymphoma. |
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| Anaplastic large cell lymphomas, Primary systemic (T/Null cell type). |
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| World Health Organization (WHO) Classification of Tumors.. |
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| Alk+ CD30+ lymphomas: a distinct molecular genetic subtype of non-Hodgkin's lymphoma. |
| Morris SW, Xue L, Ma Z, Kinney MC |
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| PMID 11380391 |
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| Identification of novel fusion partners of ALK, the anaplastic lymphoma kinase, in anaplastic large-cell lymphoma and inflammatory myofibroblastic tumor. |
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| PMID 12112524 |
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| Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. |
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| PMID 12661011 |
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| Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. |
| Lamant L, Gascoyne RD, Duplantier MM, Armstrong F, Raghab A, Chhanabhai M, Rajcan-Separovic E, Raghab J, Delsol G, Espinos E |
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| PMID 12800156 |
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