| 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). |
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| 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. |
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| 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. |
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Partial GTG-banded karyotype of t(4;17)(q12;q21). |
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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). |
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| 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. |
Fusion Protein| |  |
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FIP1L1: Conserved FIP domain; RARA; DBD DNA binding domain, LBD ligand binding domain. |
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| 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. |
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| Fusion of FIP1L1 and RARA as a result of a novel t(4;17)(q12;q21) in a case of juvenile myelomonocytic leukemia. |
| Buijs A, Bruin M. |
| Leukemia. 2007 May;21(5):1104-8. Epub 2007 Feb 15. |
| PMID 17301809 |
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| Regulation of mTOR by phosphatidic acid? |
| Foster DA. |
| Cancer Res. 2007 Jan 1;67(1):1-4. |
| PMID 17210675 |
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| The seventh pathogenic fusion gene FIP1L1-RARA was isolated from a t(4;17)-positive acute promyelocytic leukemia. |
| Kondo T, Mori A, Darmanin S, Hashino S, Tanaka J, Asaka M. |
| Haematologica. 2008 Sep;93(9):1414-6. doi: 10.3324/haematol.12854. Epub 2008 Jul 4. |
| PMID 18603554 |
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| FIP1L1/RARA with breakpoint at FIP1L1 intron 13: a variant translocation in acute promyelocytic leukemia. |
| Menezes J, Acquadro F, Perez-Pons de la Villa C, Garcia-Sanchez F, Alvarez S, Cigudosa JC. |
| Haematologica. 2011 Oct;96(10):1565-6. doi: 10.3324/haematol.2011.047134. Epub 2011 Jul 12. |
| PMID 21750086 |
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| Activation of FIP1L1-PDGFRalpha requires disruption of the juxtamembrane domain of PDGFRalpha and is FIP1L1-independent. |
| Stover EH, Chen J, Folens C, Lee BH, Mentens N, Marynen P, Williams IR, Gilliland DG, Cools J. |
| Proc Natl Acad Sci U S A. 2006 May 23;103(21):8078-83. Epub 2006 May 11. |
| PMID 16690743 |
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