Chromosome 8p11 Myeloproliferative Syndrome

A number sign (#) is used with this entry because the 8p11 myeloproliferative syndrome, also known as stem cell leukemia/lymphoma (SCLL), results from translocations involving the FGFR1 gene (136350) on chromosome 8p11 with various partner genes, most often with the ZNF198 gene (ZMYM2; 602221) on chromosome 13q11.

Description

The 8p11 myeloproliferative syndrome is a rare aggressive condition characterized in its typical form by the occurrence, either simultaneously or sequentially, of a BCR/ABL-negative myeloproliferative disorder and a lymphoma, usually a precursor T-lymphoblastic lymphoma. The disease most often terminates in acute myeloid leukemia (Goradia et al., 2008).

Clinical Features

Stem cell leukemia/lymphoma syndrome usually presents as lymphoblastic lymphoma in association with a myeloproliferative disorder, often accompanied by pronounced peripheral eosinophilia and/or prominent eosinophilic infiltrates in the affected bone marrow. The disorder generally progresses to full-blown acute myelogenous leukemia within a year of diagnosis (Abruzzo et al., 1992; Inhorn et al., 1995; Macdonald et al., 1995; Michaux et al., 1996; Reither et al., 1999).

Cytogenetics

Xiao et al. (1998) noted that a specific chromosome translocation, t(8;13)(p11;q11-12), had been found in both lymphoma and myeloid leukemia cells from patients with SCLL, supporting bi-lineage differentiation from a transformed stem cell. In 4 patients with SCLL, they found that the 8p11 translocation breakpoint interrupted intron 8 of the FGFR1 gene (136350). These translocations were associated with aberrant transcripts in which 4 predicted zinc finger domains of the ZNF198 gene (602221) on chromosome 13q11 were fused to the FGFR1 tyrosine-kinase domain.

Smedley et al. (1998) likewise determined that the 8p11 translocation in patients with SCLL results in the fusion of FGFR1 to the ZNF198 gene, which they designated RAMP (rearranged in an atypical myeloproliferative disorder), at 13q11-q12. RT-PCR detected only 1 of the 2 possible fusion transcripts, encoding a product in which the N-terminal 641 amino acids of ZNF198 became joined to the tyrosine kinase domain of FGFR1. Receptor tyrosine kinases are not commonly involved in the formation of tumor-specific fusion proteins; however, previous reports of involvement of receptor tyrosine kinases in fusion products in NHL, chronic myelomonocytic leukemia, and papillary thyroid carcinoma described similar rearrangements. By analogy with these, Smedley et al. (1998) proposed that the ZNF198-FGFR1 fusion product contributed to progression of the myeloproliferative disorder by constitutive activation of tyrosine kinase function.

Popovici et al. (1998) noted that the 8p11 myeloproliferative disorder involves T- or B-cell lymphoblastic lymphoma, myeloid hyperplasia, and eosinophilia, and evolves toward acute myelogenous leukemia. This multilineage involvement suggests the malignant transformation of a primitive hematopoietic stem cell. Popovici et al. (1998) described the molecular characterization of the t(8;13) translocation that involves the FGFR1 gene and the ZNF198 gene, which they called FIM (fused in myeloproliferative disorders). The 2 reciprocal fusion transcripts, ZNF198/FGFR1 and FGFR1/ZNF198, were expressed in malignant cells. The ZNF198/FGFR1 fusion protein contained the ZNF198 putative zinc finger motifs and the catalytic domain of FGFR1, and the authors showed that the protein has a constitutive tyrosine kinase activity.

Still and Cowell (1998) presented evidence that all 9 cases of t(8;13) molecularly characterized to that time generated the same ZNF198/FGFR1 fusion protein and that there is only a single gene in 13q11 disrupted by the translocation. They also detected the reciprocal FGFR1/ZNF198 fusion product in 1 patient, albeit at a lower level than the ZNF198/FGFR1 product.

To identify the genes involved in the 8p11 translocation, Reiter et al. (1998) used fluorescence in situ hybridization (FISH) analysis to show that the chromosome 8 breakpoints fall within YAC 899e2 and that the chromosome 13 breakpoints are clustered in a region flanked by YACs 929f11 and 911h8. FISH using chromosome 13 PAC clones indicated that the t(8;13) is not simply a reciprocal translocation but also involves an inversion of 13q11-q12. Exon trapping of a PAC that spanned the chromosome 13 translocation breakpoints led to the identification of a gene, ZNF198, that detected rearranged bands when used as a probe against Southern blots of patient DNA. Conceptual translation of the full-length ZNF198 cDNA sequence predicted a protein of 1,377 amino acids that showed significant homology to 2 previously identified proteins. Alignment of these 3 proteins revealed a novel, conserved zinc finger-related motif (MYM domain) that was repeated 5 times in each protein. To identify the translocation partner gene on chromosome 8, 5-prime and 3-prime RACE polymerase chain reactions were performed on patient RNA with several combinations of ZNF198 primers. Clones were identified in which ZNF198 was fused to exon 9 of the FGFR1 gene on chromosome 8p11. An identical ZNF198/FGFR1 fusion was detected in 3 patients with a t(8;13) for whom RNA was available; reciprocal FGFR1/ZNF198 transcripts were not detected. The fusion included the 5 MYM domains of ZNF198 and the intracellular tyrosine kinase domain of FGFR1. Reiter et al. (1998) hypothesized that this fusion leads to constitutive activation of the FGFR1 tyrosine kinase in a manner analogous to the activation of ABL by BCR in chronic myeloid leukemia.

Popovici et al. (1998) noted that in this disorder the 8p11 region is associated with 3 different partners, 6q27, 9q33, and 13q12, in the formation of translocations.

Goradia et al. (2008) noted that at least 8 partner genes had been found in association with the FGFR1 gene in cases of 8p11 myeloproliferative syndrome. The partner genes included FOP/FGFR1OP (605392), CEP110 (605496), BCR (151410), HERV-K, FGFR1OP2 (608858), TIF1 (603406), and MYO18A (610067).

Animal Model

Chen et al. (2004) found that expression of the ZNF198/FGFR1 fusion tyrosine kinase in primary murine hematopoietic cells caused a myeloproliferative syndrome in mice that recapitulated the human myeloproliferative disorder phenotype. They found that a small-molecule tyrosine kinase inhibitor, PKC412, effectively inhibited ZNF198/FGFR1 tyrosine kinase activity and activation of downstream effector pathways, and inhibited proliferation of ZNF198/FGFR1-transformed Ba/F3 cells. Treatment with PKC412 resulted in statistically significant prolongation of survival in the murine model of ZNF198/FGFR1-induced myeloproliferative disorder. Based in part on these data, PKC412 was administered to a patient with t(8;13)(p11;q12) and was efficacious for a limited time in treatment of progressive myeloproliferative disorder with organomegaly.

Agerstam et al. (2010) demonstrated that retroviral expression of ZMYM2/FGFR1 or BCR/FGFR1 in human CD34+ hematopoietic cells induces an increased cellular proliferation and differentiation toward the erythroid lineage in vitro. In immunodeficient mice, both fusion oncogenes induce a myeloproferative-like disorder, accompanied by bone marrow fibrosis and blast accumulation, consistent with features observed in patients with the 8p22 myeloproliferative syndrome.