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The 8p11 myeloproliferative syndrome (EMS), also called stem cell leukemia/lymphoma (SCLL), is a relatively rare 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 which is resistant to conventional chemotherapy. The defining cytogenetic abnormality, a translocation at the 8p11 locus, always involves the fibroblast growth factor 1 (FGFR1) gene. To date, eight partner genes have been identified in association with FGFR1 rearrangements. The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198 located at 13q11. The t(8;13)(p11;q11) disrupts intron 8 of the FGFR1 gene and fuses proline-rich and zinc finger domains of the ZNF198 gene with the cytoplasmic tyrosine kinase domain of FGFR1. Oligomerization of the fusion protein occurs, with subsequent activation of downstream signal transduction pathways, culminating in neoplastic cell transformation. This review describes the historical development of the EMS/SCLL and outlines its cytogenetic abnormalities and molecular mechanisms with an illustrative case.
The occurrence of a myeloproliferative disorder in association with an aggressive lymphoproliferative disorder is a distinctly unusual phenomenon. The 8p11 myeloproliferative syndrome (EMS), also known as stem cell leukemia-lymphoma syndrome (SCLL), is a relatively rare condition characterized by a BCR/ABL-negative myeloproliferative disease and a lymphoma, often precursor-T lymphoblastic lymphoma (T-LBL). Similar to chronic myelogenous leukemia (CML), the myeloproliferative aspect has a chronic phase which transforms to a myeloblastic phase, typically within one year of diagnosis. The acute leukemia is resistant to conventional chemotherapy. The characteristic chromosomal translocation always involves the fibroblast growth factor receptor 1 (FGFR1) gene at chromosome 8p11 . Its presence in both the myeloid and lymphoid malignancies suggests bi-lineage differentiation from an affected pluripotent stem cell. Abruzzo and colleagues are generally credited with first describing the clinical features of patients with EMS/SCLL . In 1992, they reported on 3 cases of T-lymphoblastic lymphoma with associated eosinophilia and subsequent development of a myeloid malignancy, and they suggested that the former disease process carries a high risk for development of the latter. The chromosome karyotype they reported on case #2, [t(8;13)(p23;q14)], was similar to, but not the same as, the 8p11 translocation which defines EMS/SCLL. In the same year, Rao et al described a case which conforms to EMS/SCLL both cytogenetically and histologically . In 1995, Inhorn et al added 2 of their own cases to 4 cases in the medical literature and proposed that LBL with eosinophilia and myeloid hyperplasia/malignancy with t(8;13)(p11;q11) be considered a distinctive clinicopathologic entity . We report a case of a patient with EMS/SCLL and review the medical literature on this topic.
A 39 year old man presented with inguinal lymphadenopathy, leg swelling, and a 20 pound weight loss over the prior six months. A CT scan demonstrated multiple bilateral pulmonary nodules and prominent intra-abdominal and pelvic lymphadenopathy. No involvement of the mediastinum was noted. Biopsy of an inguinal lymph node in May of 2006 demonstrated a diffuse infiltrate composed of intermediate-sized mononuclear cells with scant cytoplasm and large round nuclei with fine chromatin, suggestive of hematopoietic blasts (Figure 1). Large numbers of eosinophils were admixed with the neoplastic cells. Immunohistochemical stains and flow cytometric analysis demonstrated that the malignant cells were positive for CD2, CD5, CD7, terminal deoxyribonucleotidyl transferase (TdT) with co-expression of CD4 and CD8, findings consistent with a diagnosis of T-LBL. Bone marrow aspirate and biopsy showed no overt abnormalities.
The patient began therapy with the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin and dexamethasone) regimen , receiving a total of 2.5 cycles of treatment. His disease responded only partially and then progressed. He was switched to the Larson regimen , received an induction course and two intensification courses, and achieved a good partial response.
In December of 2006, his white blood count was noted to be persistently elevated. Complete blood count (CBC) showed hemoglobin 112 g/L; platelet count 118,000/μL; and WBC 18,500/μL with 32% neutrophils, 13% bands, 4% metamyelocytes, 2% myelocytes, 15% monocytes, 9% eosinophils, and 25% lymphocytes. Peripheral blood smear confirmed a prominent myeloid left shift, monocytosis and eosinophilia.
Repeat bone marrow aspirate and biopsy showed a hypercellular (~90%) marrow (Figure 2A) with active and left-shifted granulopoiesis, marked dysplasia of the erythroid (Figure 2B) and myeloid lineages, and moderate eosinophilia (Figure 2C). An iron stain showed an increase in ringed sideroblasts. Blasts were not increased. Cytogenetic analysis of the bone marrow aspirate showed the following karyotype: 47, XY, t(8;13)(p11;q12), +21 . A diagnosis of chronic myelomonocytic leukemia was made. Because of the recent diagnosis of T-LBL and the above chromosome karyotype, it was concluded that the patient had the 8p11 myeloproliferative syndrome. He was treated with two cycles of ifosfamide, carboplatin and etoposide with progression of his disease.
By March 2007, his CBC was as follows: hemoglobin 96 g/L; platelet count 49,000/μL; and WBC 2,900/μL with 72% neutrophils, 1% bands, 17% monocytes, 1% eosinophils, and 9% lymphocytes. Bone marrow aspirate (Figure 3A) and biopsy (Figure 3B) at this time were hypercellular (~90%) with increased, left-shifted and dysplastic myelopoiesis and monopoiesis including 18% blasts and 7% promonocytes, sufficient for a morphological diagnosis of acute myelomonocytic leukemia (AMML). Flow cytometry of this specimen confirmed increased myelomonoblasts uniformly expressing CD4, CD13, CD33, CD34 and HLA-DR, with dim CD45 expression and low side scatter. Approximately one-third of these blasts also coexpressed CD19, CD10 and TdT (Figure 4), compatible with B-lymphoblastic differentiation. Monocytes were also increased; a large subset showed aberrant coexpression of CD56.
In May 2007, the patient underwent full allogeneic stem cell transplantation from an HLA-matched sibling. His course was complicated by cutaneous graft-versus-host disease and deep venous thrombosis. By July 2007, his leukemia had recurred with marrow and meningeal involvement. He elected supportive care in hospice, where he expired 14 months after his initial diagnosis.
The case detailed above exhibits many features typical of the EMS/SCLL, including male sex; constitutional symptoms at presentation; an aggressive lymphoma with generalized lymphadenopathy which spares the mediastinum (splenomegaly and variable hepatomegaly are also frequent findings); peripheral blood neutrophilic leukocytosis and eosinophilia during the course of the disease; development of acute myeloid leukemia (AML) which is resistant to standard chemotherapy; and a chromosome karyotype with the defining 8p11 translocation.
There are numerous variations on the above theme. Patient age has been reported as low as 3 years  and as high as 84 years . Females constitute approximately 40% of the cases. Mediastinal lymphadenopathy, generally considered to be absent in the typical EMS, has been reported at least twice [2, 9]. Lymphadenopathy limited to a single region can also occur . The CBCs noted usually at the time of diagnosis are very variable, reflecting the particular hematologic entity present. Hemoglobin (Hgb) levels are generally well-maintained, with several reports of elevated Hgb values and/or red blood cell counts without mention of polycythemia vera [9, 11-13]. The platelet count is only rarely noted to be elevated .
Bone marrow morphology early in EMS/SCLL, while most often displaying features of an atypical myeloproliferative disorder, may show considerable variability. Findings consistent with chronic myelomonocytic leukemia have been noted in at least several patients [3, 14, 15]. In one unusual case, a 20 year old man was reported to have had pre-existing polycythemia vera for 8 years before transformation to AML-M4 with t(6;8)(q27; p11) . Several cases with marrow findings of AML at the time the diagnosis of EMS/SCLL was made have been reported, either alone [17, 18], concurrent with T-LBL , or as a bi-lineal acute leukemia together with precursor B acute lymphoblastic leukemia (B-ALL) [19, 20]. In at least 3 instances, ALL alone has been the presenting disorder, including 2 cases of B-ALL [10, 11] and one case of precursor T-acute lymphoblastic leukemia (T-ALL) . Lymph node findings at diagnosis have been more uniform, with most cases demonstrating morphologic and phenotypic features of T-LBL with or without eosinophils. Rare cases have demonstrated findings consistent with myeloid (granulocytic) sarcoma [4, 22].
When EMS/SCLL was first identified as a syndrome in the early-mid 1990's, cases were included which met both cytogenetic and clinical criteria, namely a translocation involving 8p11-12 and usually 13q11-12 as well as an atypical myeloproliferative syndrome diagnosed simultaneously with or in close temporal relationship to an immature T-cell lymphoma. Except for occasional patients who underwent bone marrow or peripheral stem cell transplantation, these patients typically developed and succumbed to AML. In more recent years, the designation of EMS has been applied to any case in which a translocation involving 8p11-12 (FGFR1) has been demonstrated. At least 8 partner genes in the FGFR1 translocation have been identified [1, 15–17, 19, 23–26], and the clinical manifestations are nearly as varied as the number of reported cases. For example, two patients, one with T-LBL and a myeloproliferative disorder with features of polycythemia vera, the other with an atypical myeloproliferative disorder alone, developed B-ALL [9, 13]. Another patient developed sequentially B-ALL, a chronic myeloproliferative disorder, and AML . Our case and case #1 of Etienne et al  started with a T-cell lymphoma and ultimately developed a biphenotypic acute leukemia with features of AML and B-ALL. One patient with an atypical myeloproliferative disorder and a “T-cell lymphoma” developed chronic myelomonocytic leukemia and eventually died of “stem cell leukemia” . At least 3 cases with the 8p11-12 translocation have been reported [15, 17, 18] in which the only manifestation of the EMS was a myeloid neoplasm without a lymphoid component.
Prior to 1992, sporadic cases of balanced rearrangements involving the proximal short arm of chromosome 8 were reported in association with hematologic malignancies. As noted above, in 1992, Abruzzo and colleagues were the first to suggest that T-LBL with eosinophilia may represent a specific clinical entity . Subsequently, single case reports and small series began to appear detailing T or B cell lymphoblastic lymphomas in association with myeloid disorders, occurring either concurrently or sequentially, and exhibiting t(8;13)(p11-12;q11-12). The term “8p11 myeloproliferative disorder” was first used by Macdonald et al in 1995 .
The original and most common translocation associated with EMS, the t(8;13), creates a fusion transcript composed of the zinc finger and proline rich motif of ZNF198 and the tyrosine kinase domain of FGFR1. A detailed review of the structure and function of the FGFR1 is provided by Groth and Lardelli . In brief, the FGFR1 gene located at 8p11.1-11.2 has 19 exons leading to several splice variants and isoforms. The longest product codes for a transmembrane receptor with 2 or 3 immunoglobulin-like extracellular domains, a single pass transmembrane domain and an intracellular tyrosine kinase domain . In the presence of extracellular ligand, wild type transmembrane FGFR1 undergoes conformational change and forms homodimers with intracellular tyrosine kinase activity, leading to activation of several effector pathways including STAT1 and STAT5, PI3K, PLC-γ and MAP-kinase .
The most frequent FGFR1 translocation partner is the zinc finger gene ZNF198 located at 13q11. Wild type ZNF198 codes for a 1377 amino acid, 150 kDa protein  that is predominantly localized to the nucleus. It contains five zinc finger domains, a proline-rich domain and a C-terminal acidic domain containing a potential nuclear localization signal. The zinc finger domains and proline rich domain are conserved in ZNF198-FGFR1 fusions, whereas the nuclear localization signal is lost. As opposed to the usual zinc finger proteins that function as DNA-binding transcription factors, the zinc finger domains found in ZNF198 are thought to have a role in protein-protein interactions .
The t(8;13)(p11;q11) translocation disrupts intron 8 of the FGFR1 gene and fuses five zinc finger domains and the proline-rich domain of the ZNF198 gene with the cytoplasmic tyrosine kinase domain of FGFR1 . Xiao et al demonstrated that the proline-rich motifs and not the zinc finger domains are required for oligomerization of the fusion protein, the mechanism thought to underlie the constitutive tyrosine kinase activation essential to the pathogenesis of EMS . Whereas native FGFR1 is tethered to the cell membrane, the ZNF198-FGFR1 fusion protein and other FGFR1 translocation products are found in the cytoplasm . Subsequent activation of various downstream signal transduction pathways, notably STAT 5 , culminates in unregulated cell proliferation and neoplastic transformation.
To date, eight partner genes have been identified in association with FGFR1 rearrangements in the EMS/SCLL (Table 1). They include ZNF198 at 13q11-12 , FOP/FGFR1OP at 6q27 , CEP110 at 9q33 , BCR at 22q11 [17, 24], HERV-K at 19q13 , FGFR1OP2 at 12p11 , TIF1 at 7q34  and MYO18A at 17q23 . When partner genes other than ZNF198 [e.g., BCR in the t(8;22), CEP110 in the t(8;9), FOP in the t(6;8)] are involved in the translocation with FGFR1, oncogenic mechanisms similar to those activated by the ZNF198-FGFR1 protein are believed to be operative, with homodimerization motifs imparted by different protein domains [17, 35]. All of the fusion transcripts studied thus far have been shown to have constitutive, ligand-independent tyrosine kinase activity and to transform Ba/F3 murine hematopoietic cell lines [30, 36–38]. Known phosphorylation targets of native FGFR1, including STAT5, PI3K and PLC-γ, are phosphorylated in ZNF198-FGFR1 cell lines and are thought to induce neoplastic transformation. In addition, a dominant negative interaction between ZNF198-FGFR1 and endogenous wild-type ZNF198 occurs which is associated with failure of PML body formation has been proposed as an oncogenic mechanism . Genetic loci which are suspected of being rearrangement partners for FGFR1 and which have not yet undergone molecular characterization include 17q25, 11p15 and 12q15 .
Expression of the ZNF198-FGFR1 fusion gene in mouse models leads to a myeloproliferative disorder and a T cell lymphoma, recapitulating the components of human EMS [31, 40]. Furthermore, the t(6;8) associated with the FOP-FGFR1 fusion gene induces myeloproliferative disorders in murine models . A small molecule tyrosine kinase inhibitor of many protein kinases, PKC412 (N-benzoyl-staurosporine), was shown to inhibit ZNF198-FGFR1 activity in cell lines, leading to prolonged survival in a mouse model of EMS and to clinical control of disease for a limited period of time in a single patient with EMS . These results raise the possibility that small molecule tyrosine kinase inhibitors that specifically target FGFR1 fusion proteins may be available in the future for patients with EMS, analogous to the use of imatinib for CML.
In contrast to the SCLL/EMS phenotype, two additional but clinically and genetically distinct myeloid leukemias have been described involving the 8p11-12 chromosomal locus. Several patients with a myeloproliferative disorder resembling Philadelphia chromosome-positive chronic myelogenous leukemia (Ph+ CML) have been found to harbor a t(8;22)(p11;q11) involving the FGFR1 and BCR genes [17, 24]. These patients do not manifest involvement of the lymphoid lineage as seen with other FGFR1 translocations. Translocations involving 8p11 are also identified in a small percentage of patients with de novo acute myeloid leukemia. These leukemias usually display monocytic differentiation with M4/M5 phenotype and are frequently associated with extensive erythrophagocytosis. In these cases, the MOZ gene, also located at 8p11-12, is involved in the translocation rather than FGFR1 . The t(8;16)(p11;p13) involving the MOZ-CBP fusion is the archetype of this family of tumors.
In compiling the reported karyotypes involved in the SCLL/EMS (Table 2), it has become evident that gain of an additional copy of chromosome 21 is a non-random cytogenetic event apparently associated with progression of this disease. This abnormality is reported in only 5 of 47 (10.6%) karyotypes from the time of diagnosis but in10 of 13 (76.9%) karyotypes reported in follow-up. These karyotypes were mostly derived during clinical deterioration. Thus we agree with a recently-stated proposition by Agerstam et al that trisomy 21 appears to be a non-random cytogenetic event which is associated with progression of disease in patients with the EMS/SCLL . Our case did not have conventional cytogenetics performed at diagnosis but did show a +21 in addition to the t(8;13) in follow-up at the time of the subsequent diagnosis of AMML.
We would like to thank Ms. Colette R. Grandstaff for her administrative assistance.
This case has been presented at the 2nd Annual Atlantic Regional Hematopathology Meeting in Philadelphia, PA, May 19, 2007.