Clinical entity defined by the disruption of the FGFR1 gene located at 8p11 with generation of a fusion gene between the 3 part of FGFR1 and the 5 part of the partner gene that also provides its promoter. The partner gene is always expressed in the haematopietic system and codes for a protein with oligomerization domains. As a result of oligomerization, chimeric proteins show constitutive and ligand-independent activation of FGFR1 kinase activity.
The 8p11 myeloproliferative syndrome (EMS) is a myeloproliferative disease with multilineage involvement characterized by chronic myelomonocytic leukemia (CMML)-like myeloid hyperplasia, marked peripheral blood eosinophilia and associated with a high incidence of non-Hodgkins lymphoma, usually of the T-cell lymphoblastic subtype. Occasional cases also show a B-cell lymphoproliferative disorder (Macdonald et al., 2002).
EMS cases were already described in the 1970s and 1980s, but cytogenetic and molecular analyses were not available (Manthorpe et al., 1977; Kjeldsberg et al., 1979; Catovsky et al., 1980; Posner et al., 1982). In 1992, 3 cases of T-cell lymphoblastic lymphoma associated with eosinophilia that subsequently developed acute myeloid leukemia or myelodysplastic/myeloproliferative neoplasms were reported (Abruzzo et al., 1992). One of them showed a t(8;13) by conventional cytogenetics. Later it was shown that one of the breakpoints involved one 8p11 locus (Xiao et al., 1998). In the same year, Rao et al. reported a patient with t(8;13)(p11;q12) who presented with leukocytosis, monocytosis, myeloid hyperplasia of bone marrow, and generalized lymphadenopathy due to T-cell lymphoblastic lymphoma (Rao et al., 1998). The term 8p11 myeloproliferative syndrome was suggested in 1995 by Macdonald et al. (Aguiar et al., 1995; Macdonald et al., 1995) and confirmed as clinical entity (SCLL) by Inhorn et al. (Inhorn et al., 1995).

The presence of the cytogenetic aberration in 8p11 both in myeloid and lymphoid cells, suggest a bilineage differentiation from a pluripotent and common stem cell (Macdonald et al., 2002).

The FGFR1 fusion proteins that result from chromosomal translocations affecting 8p11 have constitutive and ligand-independent FGFR1 enzymatic activity. FGFR1 is a receptor tyrosine kinase that dimerizes upon ligand binding, activating multiple signalling pathways like Ras/MAPK, PI3K, PLCgamma and STAT. These pathways could be abnormally activated as consequence of FGFR1 aberration (Macdonald et al., 2002) resulting in cell transformation. In fact, expression of ZMYM2-FGFR1 and BCR-FGFR1 fusions in immunodeficient mice are capable of initiating an EMS-like disease (Agerstam et al., 2010). Different fusion proteins could activate these pathways in a different way and could explain the phenotypic variability of the disease (Roumiantsev et al., 2004; Cross and Reiter, 2008; Jackson et al., 2010).

This is a very rare disease with less than 100 patients reported around the world and it can be found at any age. It has been reported at ages ranging from 3 to 84 years (median: 44 years). There is a slightly male-to-female predominance (Macdonald et al., 2002; Jackson et al., 2010).

Around 20-25% of patients show systemic and unspecific symptoms like fatigue, night sweats, weight loss and fever and around 20% are asymptomatic (and the disease is detected in routine analyses). Near two thirds of patients show lymphadenopathy, generalized or localized. Hepato- and/or splenomegaly are also frequent events in these patients. One of the distinctive features of this disease is the high frequency of lymphoblastic lymphoma, uncommon in other myeloproliferative neoplasms (Macdonald et al., 2002; Jackson et al., 2010).

It seems that neoplastic cells present in lymph nodes are predominantly small or medium lymphoblasts with a small cytoplasm (Jackson et al., 2010).

The blood counts reported are variable. More than 90% of patients have leukocytosis and less than 10% have leukopenia but some cases have been reported with normal leukocyte counts. Eosinophilia is frequent, but monocytosis appears only in one third of patients. Basophils are increased only in cases with the t(8;22)(p11;q11). Blasts have been detected in half of the patients and some cases show blast counts typical of an acute leukemia. These blasts are mainly of a myeloid or myeloid and lymphoid (bilineal) lineage although some of them are also of an immature lymphoid lineage.
Most of the patients show a hypercellular bone marrow that leads to a diagnosis of myeloid hyperplasia or a myeloproliferative neoplasm. But in some cases, the dysplastic features lead to a diagnosis of myelodysplastic syndrome or a myelodisplastic syndrome/myeloproliferative neoplasm.
Most of the cases with lymph node biopsies reported had T-lymphoblastic lymphoma and the rest had myeloid sarcoma. In some cases evidence of bilineal T-cell/myeloid or B-and T- cell lymphoblastic lymphoma has been reported. For a review see Jackson et al., 2010.

This is a very aggressive disease with a high rate of progression to an AML resistant to conventional chemotherapy with a median survival time of less than 12 months (Macdonald et al., 2002; Cross and Reiter, 2008; Jackson, 2010).
There are very few cases (Martinez-Climent et al., 1998; Zhou et al., 2010) responding to interferon alpha, this treatment could be useful at early stages. However, to date, only stem cell transplant remains effective to eradicate or suppress the malignant clone (Macdonald et al., 2002; Jackson et al., 2010). Median survival time for patients who received transplant after transformation to AML is 24 months (range 6-46 months) but median survival time is 12 months for the patients who did not received transplant (range 0-60 months) (Jackson et al., 2010). Currently there are no specific inhibitors for clinical use effective in this disease. Patients with FGFR1 fusions do not respond to drugs developed for other tyrosine kinases like imatinib, although several FGFR1 inhibitors have been tested, some of them with promising effects (Zhang et al., 2010; Zhou et al., 2010; Bhide et al., 2010; Risuleo et al., 2009; Ma et al., 2008; Cai et al., 2008; Chase et al., 2007; Kammasud et al., 2007; Klenke et al., 2007; Chen et al., 2004; Aviezier et al., 2000).

This disease has a chronic phase characterized by myeloid hyperplasia and overproduction of myeloid cells that can differentiate, but without treatment the disease progresses rapidly (1 to 2 years after diagnosis) to an acute myeloid leukemia (AML) or sometimes to a B-lineage ALL (Macdonald et al., 1995; Inhorn et al., 1995; Macdonald et al., 2002; Jackson et al., 2010).
Gain of an additional copy of chromosome 21 is a non-random cytogenetic event apparently associated with progression of this disease (Agerstam et al., 2007; Goradia et al., 2008) but its role remains unclear (Jackson et al., 2010). This abnormality is reported in only 5 of 47 (10.6%) karyotypes at the time of diagnosis but in 10 of 13 (76.9%) karyotypes reported in follow-up. These karyotypes were mostly derived during clinical deterioration. In addition, some findings at the time of transformation from EMS to acute leukemia include the addition of various marker chromosomes, as well as trisomy of chromosomes 8, 9, 12 or 19 and deletions of chromosome 7 or either the 7p or 7q arms, and derivative chromosome 9 (Jackson et al., 2010).

As mentioned before, this is a devastating disease, which transforms to acute leukemia in a few months if left untreated, and in which the malignant clone cannot be eradicated by conventional chemotherapy. So at this moment, without specific FGFR1 inhibitors for clinical use, the stem cell transplant remains as the only possibility to a long-term survival (Macdonald et al., 1995; Inhorn et al., 1995; Macdonald et al., 2002; Jackson et al., 2010).

This disease is defined by the fusion of FGFR1 (8p11) with other partner genes, as consequence of a cytogenetic aberration, mainly chromosomal translocations. FGFR1 codes for a receptor tyrosine kinase. The gene fusion maintains the 3 terminal part of the FGFR1 gene (from exon 9) joined to the 5 terminal part of the partner gene. Partner genes are widely expressed and fusion genes have also this expression pattern. The chimeric gene codes for a protein which retains the TK domain from FGFR1 and oligomerization domains provided by the partner gene. This protein has a constitutive and ligand-independent activity and activates multiple signal transduction pathways.This disease is related to fusion genes between FGFR1, located in 8p11, and several partner genes. However there are some other aberrations affecting this chromosomal band and 8p12 in other neoplasms. Some acute myeloid leukemia (AML) cases have been described related to translocations affecting MYST3 (also known as MOZ) (Borrow et al., 1996; Carapeti et al., 1998; Chaffanet et al., 2000; Murati et al., 2007; Esteyries et al., 2008; Gervais et al., 2008) and WHSC1L1 (also known as NSD3) (Rosati et al., 2002; Romana et al., 2006; Taketani et al., 2009), both of them in 8p11. In addition, aberrations in 8p11-p12 are also frequent events in breast cancer, but the loci responsible are not well known (Yang et al., 2004; Garcia et al., 2005; Gelsi-Boyer et al., 2005; Pole et al., 2006; Yang et al., 2006; Yang et al., 2010).

Methods of detection
1. Conventional cytogenetics to identify translocations or other rearrangements involving 8p11.
2. Fluorescent in situ hibridization (FISH) with probes flanking or covering FGFR1 to demonstrate disruption of this gene.
3. 5 RACE PCR to identify FGFR1 partner gene.
4. RT-PCR with primers located in both genes fused.

Although "8p11 myeloproliferative syndrome" (EMS) (Macdonald et al., 1995) is the most frequent name for this disease in the literature, it must be designated as "myeloid and lymphoid neoplasm with FGFR1 abnormalities" under the current 2008 World Health Organization classification (Tefferi and Vardiman, 2008; Tefferi et al., 2009). This disease has been referred to as "stem cell leukemia/lymphoma" (SCLL) (Inhorn et al., 1995) which remark the coexistence of lymphoma, myeloid malignancy and lymphoblastic leukemia.