inv(2)(p23q13) RANBP2/ALK
t(2;2)(p23;q13) RANBP2/ALK
2014-11-01 Eul-Ju Seo
Affiliation
1.Department of Laboratory Medicine, University of Ulsan College of Medicine, Asian Medical Center, Seoul, Korea
Abstract
The fusion of the anaplastic lymphoma receptor tyrosine kinase (ALK) gene in myeloid malignancies is extremely rare. The RANBP2-ALK fusion of inv(2)(p23q13)/t(2;2)(p23;q13) combined with monosomy 7 has been reported in a few patients diagnosed with acute myelomonocytic leukemia or juvenile myelomonocytic leukemia.
Clinics and Pathology
Disease
Myeloid lineage: acute myelomonocytic leukemia, juvenile myelomonocytic leukemia
Phenotype stem cell origin
Three cases of acute myelomonocytic leukemia (AML-M4), two cases of juvenile myelomonocytic leukemia (JMML).
Epidemiology
Five cases reported to date: 3M/2F; age 3.5-75 years (median 16 years).
Clinics
The five patients with inv(2)(p23q13) or t(2;2)(p23;q13) were two women (31, 75 years) and one 16 year-old male with acute myelomonocytic leukemia, and two boys (3.5, 8 years) with juvenile myelomonocytic leukemia.
The median WBC was 85.3 x 109/L (range, 55.6-143.6 x 109/L) and median monocyte count was 27 x 109/L (range, 20-55 x 109/L).
The median WBC was 85.3 x 109/L (range, 55.6-143.6 x 109/L) and median monocyte count was 27 x 109/L (range, 20-55 x 109/L).
Cytology
Bone marrow: marked hypercellularity, granulocytic hyperplasia with leukemic blasts of myelomonocytic morphology.
Immunohistochemistry for ALK protein: strong staining of the nuclear membrane in leukemic cells.
Immunohistochemistry for ALK protein: strong staining of the nuclear membrane in leukemic cells.
Prognosis
In four cases, early relapse after 1 to 6 months; in two cases, early death after 2 and 14 months. Two pediatric patients were alive at 6 and 8 years after stem cell transplantation.
Cytogenetics
Cytogenetics morphological
Four out of five cases showed inv(2)(p23q13), and one case of JMML had t(2;2)(p23;q13). Interestingly, the monosomy 7 abnormality was observed in all cases, while it has not yet been reported in IMT cases.
FISH with ALK break apart probe. A split signal indicates pericentric inversion in the inv(2)(p23q13), showing ALK gene rearrangement. Courtesy Eul-Ju Seo.
Additional anomalies
Monosomy 7 (100%).
Genes Involved and Proteins
Gene name
ALK (anaplastic lymphoma receptor tyrosine kinase)
Location
2p23
Protein description
1620 amino acids; 177 kDa; receptor tyrosine kinase.
Gene name
RANBP2 (RAN binding protein 2)
Location
2q12.3
Protein description
3224 amino acids; 358 kDa; large RAN-binding protein that immunolocalizes to the nuclear pore complex; E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I. Involved in facilitation of protein import and export, sumoylation of protein cargoes, intracellular trafficking, and energy maintenance.
Result of the Chromosomal Anomaly
Description
5 RANBP2 - 3 ALK.
Transcript
In-frame fusion transcript between RANBP2 exon 18 and ALK exon 20 in all cases.
Description
1430-amino acid RANBP2-ALK fusion protein; The first 867 N-term amino acids of RANBP2 fused to the 563 C-term amino acids of ALK (i.e. the leucine-rich domain, including the leucine zipper, of RANBP2 and the entire cytoplasmic portion of ALK with the tyrosine kinase domain).
Expression localisation
Nuclear membrane.
Oncogenesis
RANBP2 protein contains an N-terminal 700-residue leucine-rich region predicted to mediate homo-oligomerization of the RANBP2-ALK oncoprotein, leading to the activation of the ALK kinase catalytic function.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 32914017 | 2019 | Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors. | 63 |
| 32684628 | 2020 | CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma. | 59 |
| 37035183 | 2023 | Case report: Epithelioid inflammatory myofibroblastic sarcoma treated with an ALK TKI ensartinib. | 44 |
| 39703852 | 2024 | Rare giant epithelioid inflammatory myofibroblastic sarcoma of the abdominal cavity in a child: a case report and review of the literature. | 43 |
| 28535796 | 2017 | Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma. | 32 |
| 31933992 | 2019 | Epithelioid inflammatory myofibroblastic sarcoma of stomach: diagnostic pitfalls and clinical characteristics. | 25 |
| 27874193 | 2017 | ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma. | 24 |
| 27460384 | 2016 | Epithelioid inflammatory myofibroblastic sarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature. | 24 |
| 21030459 | 2010 | The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers. | 20 |
| 26097614 | 2015 | Epithelioid inflammatory myofibroblastic sarcoma in abdominal cavity: a case report and review of literature. | 13 |
| 26893756 | 2016 | Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement with bland cytological features mimicking desmoid-type fibromatosis: A case report and review of the literature. | 12 |
| 26823889 | 2015 | Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: a case report and review of literature. | 9 |
| 37398940 | 2023 | Epithelioid inflammatory myofibroblastic sarcoma: a pitfall in the differential diagnosis of ALK-positive anaplastic large cell lymphoma. | 3 |
| 24613277 | 2014 | RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia. | 0 |
| 33491794 | 2023 | Characteristic nuclear membrane ALK reactivity in chronic myelomonocytic leukemia with RANBP2-ALK fusion. | 0 |
| 24470379 | 2014 | Identification of RANBP2-ALK fusion in ALK positive diffuse large B-cell lymphoma. | 0 |
| 29437595 | 2018 | Integrated molecular profiling of juvenile myelomonocytic leukemia. | 0 |
| 34816804 | 2022 | Primary Cutaneous Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring RANBP2-ALK Fusion: Report of an Exceptional Case. | 0 |
| 12661011 | 2003 | Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor. | 0 |
| 25766836 | 2015 | Crizotinib resistance in acute myeloid leukemia with inv(2)(p23q13)/RAN binding protein 2 (RANBP2) anaplastic lymphoma kinase (ALK) fusion and monosomy 7. | 0 |
| 33677881 | 2021 | [Clinicopathological features of inflammatory myofibroblastic tumor]. | 0 |
| 25028698 | 2014 | A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib. | 0 |
| 35543076 | 2022 | Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy. | 0 |
| 38155480 | 2024 | Abdominal inflammatory myofibroblastic tumour: Clinicopathological and molecular analysis of 20 cases, highlighting potential therapeutic targets. | 0 |
| 31578734 | 2020 | Diagnostic utility of pan-Trk immunohistochemistry for inflammatory myofibroblastic tumours. | 0 |
| 34138797 | 2022 | Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases. | 0 |
| 24307515 | 2014 | inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman. | 0 |
| 28787324 | 2018 | Epithelioid Inflammatory Myofibroblastic Sarcoma of the Ovary With RANB2-ALK Fusion: Report of a Case. | 0 |
| 21164297 | 2011 | Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 24613277 | 2014 | RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia. | Lim JH et al |
| 24307515 | 2014 | inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman. | Maesako Y et al |
| 20428197 | 2010 | ALK fusion genes in children with atypical myeloproliferative leukemia. | Röttgers S et al |
Summary
Fusion gene
RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) COF 415 416 417 418|RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) M inv(2)(p23q13) t(2;2)(p23;q13)|RANBP2/ALK RANBP2 (2q12.3) ALK (2p23.2) TIC
Note
The inv(2)(p23q13) is an example of two variants involving ALK gene at 2p23 and RANBP2 gene at 2q13, inv(2) and t(2;2). The RANBP2/ALK fusion combined with monosomy 7 is associated with myeloid malignancies. This chromosomal rearrangement has also been observed in inflammatory myofibroblastic tumors (IMT).
inv(2)(p23q13) G-banding. Courtesy Eul-Ju Seo.
Citation
Eul-Ju Seo
inv(2)(p23q13) RANBP2/ALK
t(2;2)(p23;q13) RANBP2/ALK
Atlas Genet Cytogenet Oncol Haematol. 2014-11-01
Online version: http://atlasgeneticsoncology.org/haematological/1710/t(2
