t(4;17)(q12;q21) FIP1L1/RARA

2014-10-01   Adriana Zamecnikova  

1.Kuwait Cancer Control Center, Laboratory of Cancer Genetics, Department of Hematology, Shuwaikh, 70653, Kuwait
2.Department of Medical Genetics, University Medical Center Utrecht. PO BOX 85090, 3508 AB Utrecht, The Netherlands

Abstract

Review on t(4;17)(q12;q21) FIP1L1/RARA, with data on clinics, and the genes involved.

Clinics and Pathology

Disease

Juvenile myelomonocytic leukemia (JMML) and acute promyelocytic leukemia (APL)

Epidemiology

Only 3 cases reported; a 1 year old male patient with JMML (Buijs and Bruin, 2007) and 2 females aged 77 and 90 years diagnosed with APL (Kondo et al., 2008; Menezes et al., 2011).
Atlas Image
Morphology of JMML. Bone marrow smears were stained with May-Grünwald-Giemsa and shown at 1000-fold magnification. Bd=band, Bl=myelomonoblast, Eb=erythroblast, Mc=myelocyte, Mo=monocyte, Pm=promyelocyte, Se=segmented neutrophylic granulocyte.

Evolution

Sole anomaly at diagnosis in a JMML patient that evolved to complex karyotype at relapse: 45,XY,-4,t(4;17)(q12;q21), add(5)(p15),del(7)(q22), -9, -16, -17, +3mar[19]/46,XY[5]. Karyotype of patients with APL: 47,XX,t(4;17)(q12;q21),+8 (Menezes et al., 2011) and 44,X,add(X)(p?),-2,t(4;17)(q12;q21),-4,-16 (Kondo et al., 2008).

Prognosis

Unknown, as only rare cases reported. The patient with JMML succumbed after two SCT. In patients with APL, FIP1L1-RARA had an ATRA response similar to that of PML-RARA.

Cytogenetics

Atlas Image
Partial GTG-banded karyotype of t(4;17)(q12;q21).
Atlas Image
FISH analysis using probe LSI RARA DC resulting in a fusion signal on chromosome 17 band q21, with a split 5 RARA red signal on der(17) and a 3 RARA green signal on der(4) (left panel). FISH analysis narrowing the 4q12 breakpoint to the proximity of FIP1L1 by using 4q12 specific BAC probes RP11-120K16/RP11-317M1 with a fusion signal on chromosome 4 band q12, with RP11-120K16 hybridizing to der(4)(green) and RP11-317M1 hybridizing to der(17)(red) (right panel).

Variants

In APL 17q21 RARA frequent rearrangement in: t(15;17)(q22;q21), fused with PML; in related translocations, rarely observed, involve a common breakpoint in 17q21, within RARA, fused with different partners, in: t(11;17)(q23;q21), fusion with PLZF, t(5;17)(q35;q12), fusion with NPM1, in t(11;17)(q13;q21), fusion with NUMA and in dup(17)(q12q21), fusion with Stat5b. In myeloproliferative disease CEL (Chronic eosinophilic leukemia) 4q12 FIP1L1 rearrangement: fusion to PDGFRA due to 800 Kb interstitial deletion.

Genes Involved and Proteins

Gene name
FIP1L1 (factor interacting with PAPOLA and CPSF1)
Location
4q12
Protein description
FIP1L1 is a subunit of the cleavage and polyadenylation specific factor (CPSF) complex that binds to U-rich elements via arginine-rich RNA binding motif and interacts with poly(A)polymerase (PAP).
Gene name
RARA (Retinoic acid receptor, alpha)
Location
17q21.2
Protein description
Wide expression; nuclear receptor; binds specific DNA sequences: HRE (hormone response elements); ligand and dimerization domain; role in growth and differentiation.

Result of the Chromosomal Anomaly

Description

In-frame fusion of exon 15 of FIP1L1 to exon 3 of RARA (Buijs and Bruin, 2007; Kondo et al., 2008) or with exon 13 of the FIP1L1 gene (Menezes et al., 2011).

Transcript

5FIP1L1-3RARA and 5RARA-3FIP1L1.
Atlas Image
FIP1L1: Conserved FIP domain; RARA; DBD DNA binding domain, LBD ligand binding domain.

Description

The fusion mRNA would encode a 832 amino acids FIP1L1/RARA chimeric protein containing the 428 amino-terminal amino acids of FIP1L, including the FIP homology domain and 403 carboxyl-terminal amino acids of RARA, including the DNA and ligand binding domains, with replacement of FIP1L1 amino acid 429 (Valine) and RARA amino acid 60 (Threonine) into an Alanine.

Oncogenesis

All known chimeric RARA fusion proteins provide additional homodimerization motifs, promoting formation of chimeric homodimers and thereby removing requirement of RXR for RARA to bind DNA. The homodimerization ability of RARA fusion proteins is critical for leukemic transformation. Recently, it was shown in a murine system that retroviral transduced FIP1L1/PDGFRA mediated transformation in vitro and in vivo, is FIP1L1 independent and results from disruption of the autoinhibitory JM domain of PDGFRA. However, observations using retroviral transduced FIP1L1/PDGFRA and FIP1L1/PDGFRA with an N-terminal deletion of the FIP1L1 moiety showed differences with respect to cytokine-independent colony formation and activation of multiple signalling pathways in human primary hematopoietic precursor cells, indicating that FIP1L1 contributes to FIP1L1/PDGFRA resulting in a myeloproliferative phenotype. Therefore the function of the FIP1L1 moiety remains to be resolved.

Highly cited references

Pubmed IDYearTitleCitations
186035542008The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia.31
217500862011FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia.11
247635142014FIP1L1 presence in FIP1L1-RARA or FIP1L1-PDGFRA differentially contributes to the pathogenesis of distinct types of leukemia.10
339579992021Current views on the genetic landscape and management of variant acute promyelocytic leukemia.5
342497382021Myeloid Sarcoma Type of Acute Promyelocytic Leukemia With a Cryptic Insertion of RARA Into FIP1L1: The Clinical Utility of NGS and Bioinformatic Analyses.1
358195172022EAHP 2020 workshop proceedings, pediatric myeloid neoplasms.0
345510742022Successful treatment and integrated genomic analysis of an infant with FIP1L1-RARA fusion-associated myeloid neoplasm.0

Article Bibliography

Pubmed IDLast YearTitleAuthors
173018092007Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia.Buijs A et al
172106752007Regulation of mTOR by phosphatidic acid?Foster DA et al
186035542008The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia.Kondo T et al
217500862011FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia.Menezes J et al
166907432006Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent.Stover EH et al

Summary

Fusion gene

FIP1L1/RARA FIP1L1 (4q12) RARA (17q21.2) M|FIP1L1/RARA FIP1L1 (4q12) RARA (17q21.2) M t(4;17)(q12;q21)|FIP1L1/RARA FIP1L1 (4q12) RARA (17q21.2) TIC

Citation

Adriana Zamecnikova

t(4;17)(q12;q21) FIP1L1/RARA

Atlas Genet Cytogenet Oncol Haematol. 2014-10-01

Online version: http://atlasgeneticsoncology.org/haematological/1470/gene-explorer/css/js/_common.js

Historical Card

2007-09-01 t(4;17)(q12;q21) FIP1L1/RARA by  Arjan Buijs,Marrie Bruin 

Department of Medical Genetics, University Medical Center Utrecht. PO BOX 85090, 3508 AB Utrecht, The Netherlands