| Disease | Juvenile myelomonocytic leukemia |
| Epidemiology | So far 1 case known. |
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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 | At relapse: 45,XY,-4,t(4;17)(q12;q21), add(5)(p15),del(7)(q22), -9, -16, -17, +3mar[19]/46,XY[5] |
| Prognosis | Patient succumbed after two SCT. |
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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 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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| 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 |
| Proceedings of the National Academy of Sciences of the United States of America. 2006 ; 103 (21) : 8078-8083. |
| PMID 16690743 |
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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 : official journal of the Leukemia Society of America, Leukemia Research Fund, U.K. 2007 ; 21 (5) : 1104-1108. |
| PMID 17301809 |
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| Regulation of mTOR by phosphatidic acid? |
| Foster DA |
| Cancer research. 2007 ; 67 (1) : 1-4. |
| PMID 17210675 |
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