HAEM4:Myeloid/Lymphoid Neoplasms with FGFR1 Rearrangement

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Primary Author(s)*

Yanna Ding, MD PhD

Cancer Category/Type

Myeloid/lymphoid neoplasms

Cancer Sub-Classification / Subtype

Myeloid/lymphoid neoplasms with eosinophilia and gene rearrangement

Definition / Description of Disease

Myeloid/lymphoid neoplasms with FGFR1 rearrangement are a heterogenous group of aggressive neoplasms with translocations involving the fibroblast growth factor receptor 1(FGFR1) tyrosine kinase gene on chromosome 8p11-12[1]. The neoplastic cells derive from a pluripotent haematopoietic stem cell and may be immature or mature[2]. Cases can present as a myeloproliferative neoplasm or as acute myeloid leukaemia, T- or B-lymphoblastic leukaemia/lymphoma or mixed-phenotype acute leukaemia. T-cell lymphoblastic lymphoma/leukemia is common, frequently with eosinophilia, and subsequently rapidly transforms into acute myeloid leukaemia.

Coexistence of atypical chronic myeloid leukaemia, BCR-ABL1-negative, with t(8;19)(p11.2;q13.1) and KIT D816V-positive systemic mastocytosis with an associated haematological neoplasm has been reported [3].

Synonyms / Terminology

8p11 myeloproliferative syndrome (EMS)

8p11 stem cell syndrome

8p11 stem cell leukaemia/lymphoma syndrome

Haematopoietic stem cell neoplasm with FGFR1 abnormalities

Myeloid and lymphoid neoplasms with FGFR1 abnormalities [2]

Epidemiology / Prevalence

The median age at disease onset is 32 years, although it can occur within a wide age range of 3-84 years [4]. There is a moderate predominance of male with male-to-female ratio of 1.5:1, unlike in myeloid/lymphoid neoplasms with PDGFRA or PDGFRB rearrangement [2].

Clinical Features

Systemic symptoms are common, including fatigue, fever, weight loss and night sweats. Some patients can be asymptomatic. Patients often present with peripheral blood eosinophilia without basophilia [1]. Cases with lymphoma features present as lymph nodes involvement and mediastinal mass; cases with myeloproliferative features present as splenomegaly and hypermetabolism. Cases can also present as acute myeloid leukaemia or myeloid sarcoma [4] [5] [6]. Extranodal sites of disease include tonsil, lung, and breast in small subsets of patients [1].

Sites of Involvement

Bone marrow, peripheral blood, lymph nodes, liver and spleen are primarily involved. Lymphoblasts or myeloid cells infiltration results in lymphadenopathy [2].

Morphologic Features

Peripheral blood: Most cases have leukocytosis with increased neutrophils, bands, metamyelocytes, and myelocytes. Circulating blasts and eosinophilia are common. Monocytosis can be found. Hemoglobin levels have ranged from 6.3 to 21 g/dL and platelet counts have ranged from 8 to 546 × 109/L[1].

Bone marrow biopsy: often hypercellularity due to increased granulocytic precursors and eosinophilia. Hypocellular cases also exist. Many cases were interpreted as myeloid hyperplasia or myeloproliferative neoplasm, including chronic myelogenous leukemia, atypical chronic myeloid leukemia, or chronic myelomonocytic leukemia. Primary diagnoses also include myelodysplastic syndrome, myelodysplastic syndrome/myeloproliferative neoplasm due to dysplasia. 16% of the cases may have 20% or more blasts, in the range of acute leukemia with blasts of a myeloid lineage or bilineal lineage in two thirds of the cases, and of pure immature lymphoid lineage in one third of the cases [7]. Lymphoblastic lymphoma is more commonly seen in patients with t(8;13)[3].

Lymph node biopsy: For patients who did undergo lymph node biopsy, 79% had T-lymphoblastic lymphoma and 21% myeloid sarcoma. Lymph nodes are infiltreated by small- or mediumsized lymphoblasts with fine or “dusty” chromatin and minimal cytoplasm. Eosinophils are frequently admixed with the lymphoblasts. Subtle myeloid component can be found in perivascular area. lymphoblastic component can be immunoreactive to TdT (terminal deoxynucleotidyl transferase), CD1a and pan-T-cell antigens while the subtle myeloid component can be positive for myeloperoxidase, CD15, CD68, CD117, lysozyme, or other myeloid-associated antigens[8] .

Basophilia can be found in cases with BCR-FGFR1 fusion [9], and in cases with t(1;8)(q31.1;p11.2)/TRP-FGFR1 fusion [10]. Polycythaemia vera has been reported in cases with t(6;8)(q27;p11.2)/FGFR1OP-FGFR1 fusion [11].

Immunophenotype

Immunophenotypic analysis is not helpful in chronic phase disease. However, in lymphoblastic leukemia/lymphoma and in acute myeloid transformation, immunophenotypic analysis is important to distinguish the lineage origins, such as B- or T- lineage, or myeloid lineage [2]. Please refer to the above section "Morphologic Features".

Chromosomal Rearrangements (Gene Fusions)

Various translocations with an 8p11 breakpoint are found. Depending on the partners, a variety of fusion genes with part of FGFR1 from 8p11 can be formed, encoding aberrant tyrosine kinases. Note: Some precise mapping has positioned FGFR1 locus to 8p12, instead of 8p11 [12].

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Prevalence
t(8;13)(p11.2;q12.1) ZMYM2-FGFR1 Most common, around 40% [13][14][15][16][17][1]
t(8;9)(p11.2;q33.2) CNTRL-FGFR1 Around 17% [1][18]
t(6;8)(q27;p11.2) FGFR1OP-FGFR1 Around 9% [1] [19]
t(8;22)(p11.2;q11.2) BCR-FGFR1 At least eight cases[20][21][22][23][24]
t(7;8)(q33;p11.2) TRIM24-FGFR1 At least two cases [25][26]
t(8;17)(p11.2;q23) MYO18A-FGFR1 At least one case[27]
t(8;19)(p11.2;q13.3) HERVK-FGFR1 At least one case [28][29]
ins(12;8)(p11.2;p11.2p22) FGFR1OP2-FGFR1 At least two cases [26][30]
t(1;8)(q31.1;p11.2) TRP-FGFR1 At least one case [31]
t(2;8)(q13;p11.2) RANBP2-FGFR1 At least one case [32]
t(2;8)(q37.3;p11.2) LRRFIP1-FGFR1 At least one case [33]
t(7;8)(q22.1;p11.2) CUX1-FGFR1 At least one case [34]
t(8;12)(p11.2;q15) CPSF6-FGFR1 At least two cases [26][35]
t(5;8)(q35;p11) SQSTM1-FGFR1 One case [36]

Characteristic Chromosomal Aberrations / Patterns

A variety of translocations involving 8p11 breakpoint. Secondary cytogenetic abnormalities also occur, most commonly trisomy 21 [2].

Genes and Main Pathways Involved

Normal FGFR1 is a transmembrane protein with an extracellular ligand-binding domain, a transmembrane domain and a cytoplasmic tyrosine kinase domain. In inactive state, FGFR1 presents as monomers in cell membrane. Binding with ligands--the fibroblast growth factors (FGFs), induces dimerization and a conformational change that partially activates the enzymatic activity leading to transphosphorylation of the key tyrosine residue, an increase in enzymatic activity, phosphorylation of additional tyrosines and subsequent phosphorylation of downstream target substrates. The signaling pathways include Ras/MAPK, P13K, PLCÁ and STAT proteins. Fusion proteins with FGFR1 mimic the initial tyrosine kinase activation and thus possess constitutive tyrosine kinase activity to activate multiple signal transduction pathways in myeloid/lymphoid neoplasms [37][38][39][40].

Diagnostic Testing Methods

Diagnosis is based on integration of morphology, immunophenotype, cytogenetics analysis and molecular analysis. Identification of translocations involving FGFR1 and the corresponding fusion genes is diagnostic in the setting of myeloid or lymphoid neoplasm with prominent eosinophilia. Conventional cytogenetic analysis is useful since almost all the translocations or insertions involving FGFR1 have been cytogenetically visible [41][1]. Translocations of FGFR1 and the associated fusion genes can be more specifically detected by two-color fluorescence in situ hybridization (FISH), and reverse transcriptase–polymerase chain reaction (RT-PCR) [16] [29][42].

Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)

Unlike myeloid/lymphoid neoplasms with PDGFRA or PDGFRB rearrangement, the prognosis for this FGFR1 associated entity is poor even for patient in the chronic phase, due to the high incidence of transformation. There is no established tyrosine kinase inhibitor therapy for myeloproliferative neoplasms with FGFR1 rearrangement. Midostaurin (PKC412) was reported to be effective in one case [43], and interferon has induced cytogenetic response in several cases [4] [44]. Nevertheless, haematopoietic stem cell transplantation should be considered even for patients in chronic phase.

Familial Forms

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Other Information

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Links

FGFR1

References

EXAMPLE Book

  1. Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.

Notes

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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 1.7 Jackson, Courtney C.; et al. (2010). "8p11 myeloproliferative syndrome: a review". Human Pathology. 41 (4): 461–476. doi:10.1016/j.humpath.2009.11.003. ISSN 0046-8177.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Bain BJ, et al., (2017). Myeloid/lymphoid neoplasms with FGFR1 rearrangement in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p77-78.
  3. ↑ 3.0 3.1 Duckworth, Christina B; et al. (2014). "Systemic mastocytosis with associated myeloproliferative neoplasm with t(8;19)(p12;q13.1) and abnormality of FGFR1: report of a unique case". International Journal of Clinical and Experimental Pathology. 7 (2): 801–807. ISSN 1936-2625. PMC 3925931. PMID 24551307.
  4. ↑ 4.0 4.1 4.2 Macdonald, Donald; et al. (2002). "The 8p11 Myeloproliferative Syndrome: A Distinct Clinical Entity Caused by Constitutive Activation of FGFR1". Acta Haematologica. 107 (2): 101–107. doi:10.1159/000046639. ISSN 0001-5792.
  5. ↑ Abruzzo, Lynne V.; et al. (1992). "T-Cell Lymphoblastic Lymphoma With Eosinophilia Associated With Subsequent Myeloid Malignancy:". The American Journal of Surgical Pathology. 16 (3): 236–245. doi:10.1097/00000478-199203000-00003. ISSN 0147-5185.
  6. ↑ Vega, Francisco; et al. (2015). "Hematolymphoid Neoplasms Associated With Rearrangements of PDGFRA, PDGFRB, and FGFR1". American Journal of Clinical Pathology. 144 (3): 377–392. doi:10.1309/AJCPMORR5Z2IKCEM. ISSN 1943-7722.
  7. ↑ Roy, Sukanya; et al. (2002). "Sequential Transformation of t(8;13)-Related Disease". Acta Haematologica. 107 (2): 95–97. doi:10.1159/000046637. ISSN 0001-5792.
  8. ↑ Somers, Gino R.; et al. (1997). "Coexistent T-Cell Lymphoblastic Lymphoma and an Atypical Myeloproliferative Disorder Associated with t(8;13)(p21;q14)". Pediatric Pathology & Laboratory Medicine. 17 (1): 141–158. doi:10.1080/15513819709168354. ISSN 1077-1042.
  9. ↑ Roumiantsev, Sergei; et al. (2004). "Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations". Cancer Cell. 5 (3): 287–298. doi:10.1016/S1535-6108(04)00053-4.
  10. ↑ Li, Feng; et al. (2012). "Identification of a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome". Genes, Chromosomes and Cancer. 51 (9): 890–897. doi:10.1002/gcc.21973.
  11. ↑ Vizmanos, José L; et al. (2004). "Clinical variability of patients with the t(6;8)(q27;p12) and FGFR1OP-FGFR1 fusion: two further cases". The Hematology Journal. 5 (6): 534–537. doi:10.1038/sj.thj.6200561. ISSN 1466-4860.
  12. ↑ Mozziconacci, Marie-Joëlle; et al. (2008). "Common features of myeloproliferative disorders with t(8;9)(p12;q33) and CEP110–FGFR1 fusion: Report of a new case and review of the literature". Leukemia Research. 32 (8): 1304–1308. doi:10.1016/j.leukres.2007.11.012.
  13. ↑ Popovici, C.; et al. (1998). "Fibroblast growth factor receptor 1 is fused to FIM in stem-cell myeloproliferative disorder with t(8;13)(p12;q12)". Proceedings of the National Academy of Sciences. 95 (10): 5712–5717. doi:10.1073/pnas.95.10.5712. ISSN 0027-8424. PMC 20444. PMID 9576949.CS1 maint: PMC format (link)
  14. ↑ Cross, Nicholas C. P.; et al. (1998). "Consistent Fusion of ZNF198 to the Fibroblast Growth Factor Receptor-1 in the t(8;13)(p11;q12) Myeloproliferative Syndrome". Blood. 92 (5): 1735–1742. doi:10.1182/blood.V92.5.1735. ISSN 0006-4971.
  15. ↑ Smedley, D (1998). "The t(8;13)(p11;q11-12) rearrangement associated with an atypical myeloproliferative disorder fuses the fibroblast growth factor receptor 1 gene to a novel gene RAMP". Human Molecular Genetics. 7 (4): 637–642. doi:10.1093/hmg/7.4.637.
  16. ↑ 16.0 16.1 Xiao, Sheng; et al. (1998). "FGFR1 is fused with a novel zinc-finger gene, ZNF198, in the t(8;13) leukaemia/lymphoma syndrome". Nature Genetics. 18 (1): 84–87. doi:10.1038/ng0198-84. ISSN 1061-4036.
  17. ↑ Bain, Barbara J.; et al. (2007-08). "Chronic Eosinophilic Leukemias and the Myeloproliferative Variant of the Hypereosinophilic Syndrome". Immunology and Allergy Clinics of North America. 27 (3): 377–388. doi:10.1016/j.iac.2007.06.001. ISSN 0889-8561. Check date values in: |date= (help)
  18. ↑ Pébusque, Marie-Josèphe; et al. (2000). "FGFR1 is fused to the centrosome-associated proteinCEP110 in the 8p12 stem cell myeloproliferative disorder with t(8;9)(p12;q33)". Blood. 95 (5): 1788–1796. doi:10.1182/blood.V95.5.1788.005k15_1788_1796. ISSN 0006-4971.
  19. ↑ Pébusque, Marie-Josèphe; et al. (1999). "The t(6;8)(q27;p11) Translocation in a Stem Cell Myeloproliferative Disorder Fuses a Novel Gene, FOP, to Fibroblast Growth Factor Receptor 1". Blood. 93 (4): 1381–1389. doi:10.1182/blood.V93.4.1381. ISSN 0006-4971.
  20. ↑ Steer, E. J.; et al. (2001). E. J. Steer, A. Demiroglu, C. Heath, E. Pourgourides, K. Taylor, M. Bentley. "The t(8;22) in chronic myeloid leukemia fuses BCR to FGFR1: transforming activity and specific inhibition of FGFR1 fusion proteins". Blood. 98: pp.468A. ISSN 0006-4971.CS1 maint: Extra text (link)
  21. ↑ Ågerstam, Helena; et al. (2007). "Fusion gene-mediated truncation ofRUNX1 as a potential mechanism underlying disease progression in the 8p11 myeloproliferative syndrome". Genes, Chromosomes and Cancer. 46 (7): 635–643. doi:10.1002/gcc.20442.
  22. ↑ Liu, Jing; et al. (2018). "8p11 Myeloproliferative syndrome with t(8;22)(p11;q11): A case report". Experimental and Therapeutic Medicine. doi:10.3892/etm.2018.6328. ISSN 1792-0981. PMC 6090294. PMID 30116393.CS1 maint: PMC format (link)
  23. ↑ Fioretos, Thoas; et al. (2001). "Fusion of the BCR and the fibroblast growth factor receptor-1 ( FGFR1 ) genes as a result of t(8;22)(p11;q11) in a myeloproliferative disorder: The first fusion gene involving BCR but not ABL: Fusion of the BCR and FGFR1 Genes". Genes, Chromosomes and Cancer. 32 (4): 302–310. doi:10.1002/gcc.1195.
  24. ↑ Pini, Massimo; et al. (2002). "A fourth case of BCR-FGFR1 positive CML-like disease with t(8;22) translocation showing an extensive deletion on the derivative chromosome 8p". The Hematology Journal. 3 (6): 315–316. doi:10.1038/sj.thj.6200201.
  25. ↑ Belloni, Elena; et al. (2005). "8p11 myeloproliferative syndrome with a novel t(7;8) translocation leading to fusion of the FGFR1 and TIF1 genes". Genes, Chromosomes and Cancer. 42 (3): 320–325. doi:10.1002/gcc.20144. ISSN 1098-2264.
  26. ↑ 26.0 26.1 26.2 Sohal, Jastinder; et al. (2001). "Identification of four new translocations involvingFGFR1 in myeloid disorders". Genes, Chromosomes and Cancer. 32 (2): 155–163. doi:10.1002/gcc.1177. ISSN 1045-2257.
  27. ↑ Walz, C; et al. (2005). "The t(8;17)(p11;q23) in the 8p11 myeloproliferative syndrome fuses MYO18A to FGFR1". Leukemia. 19 (6): 1005–1009. doi:10.1038/sj.leu.2403712. ISSN 0887-6924.
  28. ↑ Mugneret, Francine; et al. (2000). "The 8p12 myeloproliferative disorder. t(8;19)(p12;q13.3): a novel translocation involving the FGFR1 gene . SHORT REPORT". British Journal of Haematology. 111 (2): 647–649. doi:10.1046/j.1365-2141.2000.02355.x. ISSN 0007-1048.
  29. ↑ 29.0 29.1 Pébusque, Marie-Josèphe; et al. (2003). "Endogenous retroviral sequence is fused to FGFR1 kinase in the 8p12 stem-cell myeloproliferative disorder with t(8;19)(p12;q13.3)". Blood. 101 (1): 286–288. doi:10.1182/blood-2002-02-0577. ISSN 0006-4971.
  30. ↑ Grand, Effie K.; et al. (2004). "Identification of a novel gene,FGFR1OP2, fused toFGFR1 in 8p11 myeloproliferative syndrome". Genes, Chromosomes and Cancer. 40 (1): 78–83. doi:10.1002/gcc.20023. ISSN 1045-2257.
  31. ↑ Li, Feng; et al. (2012). "Identification of a novel partner gene, TPR, fused to FGFR1 in 8p11 myeloproliferative syndrome". Genes, Chromosomes and Cancer. 51 (9): 890–897. doi:10.1002/gcc.21973. ISSN 1098-2264.
  32. ↑ Mauvieux, L.; et al. (2013). "A translocation t(2;8)(q12;p11) fuses FGFR1 to a novel partner gene, RANBP2/NUP358 , in a myeloproliferative/myelodysplastic neoplasm". Leukemia. 27 (5): 1186–1188. doi:10.1038/leu.2012.286. ISSN 1476-5551.
  33. ↑ Soler, G; et al. (2009). "LRRFIP1, a new FGFR1 partner gene associated with 8p11 myeloproliferative syndrome". Leukemia. 23 (7): 1359–1361. doi:10.1038/leu.2009.79. ISSN 0887-6924.
  34. ↑ Wasag, B.; et al. (2011). "The kinase inhibitor TKI258 is active against the novel CUX1-FGFR1 fusion detected in a patient with T-lymphoblastic leukemia/lymphoma and t(7;8)(q22;p11)". Haematologica. 96 (6): 922–926. doi:10.3324/haematol.2010.036558. ISSN 0390-6078. PMC 3105656. PMID 21330321.CS1 maint: PMC format (link)
  35. ↑ Bae, Sook Young; et al. (2009). "Cytogenetic abnormality involving 8p11.2 in T-lymphoblastic lymphoma: report of a new case". Cancer Genetics and Cytogenetics. 191 (1): 57–58. doi:10.1016/j.cancergencyto.2009.02.003.
  36. ↑ Bessho, M.; et al. (2014). "A novel fusion of SQSTM1 and FGFR1 in a patient with acute myelomonocytic leukemia with t(5;8)(q35;p11) translocation". Blood Cancer Journal. 4 (12): e265–e265. doi:10.1038/bcj.2014.86. ISSN 2044-5385. PMC 4315892. PMID 25501022.CS1 maint: PMC format (link)
  37. ↑ Ollendorff, Vincent; et al. (1999). "Characterization of FIM-FGFR1, the Fusion Product of the Myeloproliferative Disorder-associated t(8;13) Translocation". Journal of Biological Chemistry. 274 (38): 26922–26930. doi:10.1074/jbc.274.38.26922. ISSN 0021-9258.
  38. ↑ Jiang, Guoqiang; et al. (2000). "Receptor-Like Protein Tyrosine Phosphatase α Homodimerizes on the Cell Surface". Molecular and Cellular Biology. 20 (16): 5917–5929. doi:10.1128/MCB.20.16.5917-5929.2000. ISSN 1098-5549. PMC 86069. PMID 10913175.CS1 maint: PMC format (link)
  39. ↑ Mason, Ivor J. (1994). "The ins and outs of fibroblast growth factors". Cell. 78 (4): 547–552. doi:10.1016/0092-8674(94)90520-7.
  40. ↑ Smedley, Damian; et al. (1999). "ZNF198-FGFR1 Transforms Ba/F3 Cells to Growth Factor Independence and Results in High Level Tyrosine Phosphorylation of STATS 1 and 5". Neoplasia. 1 (4): 349–355. doi:10.1038/sj.neo.7900035. PMC 1508104. PMID 10935490.CS1 maint: PMC format (link)
  41. ↑ A. Meloni-Ehrig (2013), The Cytogenetics of Hematologic Neoplasms in The Principles of Clinical Cytogenetics. 4th edition, Gersen, Steven L., Keagle, Martha B. ISBN 978-1-4899-9720-3, p320
  42. ↑ Cowell, John K.; et al. (1997). "Molecular Characterization of the t(8; 13)(p11;q12) Translocation Associated With an Atypical Myeloproliferative Disorder: Evidence for Three Discrete Loci Involved in Myeloid Leukemias on 8p11". Blood. 90 (8): 3136–3141. doi:10.1182/blood.V90.8.3136. ISSN 0006-4971.
  43. ↑ Chen, J.; et al. (2004). "PKC412 inhibits the zinc finger 198-fibroblast growth factor receptor 1 fusion tyrosine kinase and is active in treatment of stem cell myeloproliferative disorder". Proceedings of the National Academy of Sciences. 101 (40): 14479–14484. doi:10.1073/pnas.0404438101. ISSN 0027-8424. PMC 521956. PMID 15448205.CS1 maint: PMC format (link)
  44. ↑ Holmes, A L; et al. (1998). "Genetic analysis of Drosophila larval optic nerve development". Genetics. 148 (3): 1189–1201. ISSN 0016-6731. PMC 1460051. PMID 9539434.
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