inv(2)(p23q13) RANBP2/ALK
t(2;2)(p23;q13) RANBP2/ALK

2014-11-01   Eul-Ju Seo 

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).

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.

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.
Atlas Image
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 IDYearTitleCitations
210304592010The neuroblastoma-associated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers.136
211642972011Epithelioid inflammatory myofibroblastic sarcoma: An aggressive intra-abdominal variant of inflammatory myofibroblastic tumor with nuclear membrane or perinuclear ALK.66
126610112003Fusion of ALK to the Ran-binding protein 2 (RANBP2) gene in inflammatory myofibroblastic tumor.64
294375952018Integrated molecular profiling of juvenile myelomonocytic leukemia.28
278741932017ALK oncoproteins in atypical inflammatory myofibroblastic tumours: novel RRBP1-ALK fusions in epithelioid inflammatory myofibroblastic sarcoma.23
250286982014A case report of epithelioid inflammatory myofibroblastic sarcoma with RANBP2-ALK fusion gene treated with the ALK inhibitor, crizotinib.18
329140172019Crizotinib and Surgery for Long-Term Disease Control in Children and Adolescents With ALK-Positive Inflammatory Myofibroblastic Tumors.13
274603842016Epithelioid inflammatory myofibroblastic sarcoma: a clinicopathological, immunohistochemical and molecular cytogenetic analysis of five additional cases and review of the literature.12
268238892015Epithelioid inflammatory myofibroblastic sarcoma treated with ALK inhibitor: a case report and review of literature.11
285357962017Identification of EML4-ALK as an alternative fusion gene in epithelioid inflammatory myofibroblastic sarcoma.10
244703792014Identification of RANBP2-ALK fusion in ALK positive diffuse large B-cell lymphoma.9
260976142015Epithelioid inflammatory myofibroblastic sarcoma in abdominal cavity: a case report and review of literature.8
246132772014RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.6
243075152014inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman.5
326846282020CD30 and ALK combination therapy has high therapeutic potency in RANBP2-ALK-rearranged epithelioid inflammatory myofibroblastic sarcoma.4
287873242018Epithelioid Inflammatory Myofibroblastic Sarcoma of the Ovary With RANB2-ALK Fusion: Report of a Case.4
257668362015Crizotinib resistance in acute myeloid leukemia with inv(2)(p23q13)/RAN binding protein 2 (RANBP2) anaplastic lymphoma kinase (ALK) fusion and monosomy 7.4
315787342020Diagnostic utility of pan-Trk immunohistochemistry for inflammatory myofibroblastic tumours.3
319339922019Epithelioid inflammatory myofibroblastic sarcoma of stomach: diagnostic pitfalls and clinical characteristics.3
341387972022Uterine Inflammatory Myofibroblastic Neoplasms With Aggressive Behavior, Including an Epithelioid Inflammatory Myofibroblastic Sarcoma: A Clinicopathologic Study of 9 Cases.2
268937562016Inflammatory myofibroblastic tumor with RANBP2 and ALK gene rearrangement with bland cytological features mimicking desmoid-type fibromatosis: A case report and review of the literature.2
348168042022Primary Cutaneous Epithelioid Inflammatory Myofibroblastic Sarcoma Harboring RANBP2-ALK Fusion: Report of an Exceptional Case.1
355430762022Histologic characterization of paediatric mesenchymal neoplasms treated with kinase-targeted therapy.0
336778812021[Clinicopathological features of inflammatory myofibroblastic tumor].0
334917942021Characteristic nuclear membrane ALK reactivity in chronic myelomonocytic leukemia with RANBP2-ALK fusion.0

Bibliography

Pubmed IDLast YearTitleAuthors
246132772014RANBP2-ALK fusion combined with monosomy 7 in acute myelomonocytic leukemia.Lim JH et al
243075152014inv(2)(p23q13)/RAN-binding protein 2 (RANBP2)-ALK fusion gene in myeloid leukemia that developed in an elderly woman.Maesako Y et al
204281972010ALK 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).
Atlas Image
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/inv(2)(p23q13)-ranbp2-alk-br-t(2;2)(p23;q13)-ranbp2-alk