Ann Lab Med.  2018 Jul;38(4):296-305. 10.3343/alm.2018.38.4.296.

GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms

Affiliations
  • 1Department of Laboratory Medicine, College of Medicine, Ewha Womans University, Seoul, Korea. JungWonH@ewha.ac.kr
  • 2Department of Pathology, College of Medicine, Ewha Womans University, Seoul, Korea.
  • 3Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.
  • 4Department of Laboratory Medicine, Dongguk University Ilsan Hospital, Goyang, Korea. hjhuh@duih.org

Abstract

BACKGROUND
This study aimed to determine GATA1 expression levels to better characterize subgroups in BCR/ABL1-negative myeloproliferative neoplasms (MPNs).
METHODS
This study enrolled 49 patients diagnosed as having BCR/ABL1-negative MPN on the basis of the 2016 World Health Organization classification : nine polycythemia vera (PV), 17 essential thrombocythemia (ET), 12 prefibrotic primary myelofibrosis (prePMF), and 11 overt primary myelofibrosis (PMF). Relevant clinical and laboratory data were retrieved from the medical records. The molecular analysis of CALR and MPL mutations and quantification of JAK2 V617F allele burden were performed. GATA1 expression was assessed by an immunohistochemical assay on bone marrow biopsy. GATA1 expression was analyzed serially in 18 patients.
RESULTS
GATA1 expression decreased significantly in PMF compared with that in other subtypes, while no statistical difference was identified between ET and prePMF. GATA1 expression did not differ according to the mutation profiles or the allele burden of JAK2 V617F, but it decreased significantly in patients with overt fibrosis or leukemic transformation.
CONCLUSIONS
Our results suggest that GATA1 expression is significantly low in PMF and decreases with progressive fibrosis and possibly with leukemic transformation, although our attempt to accurately distinguish between subgroups using GATA1 immunohistochemical approach did not achieve statistical significance. A large patient cohort with long term follow-up is required to evaluate the prognostic value of GATA1 expression.

Keyword

Polycythemia vera; Essential thrombocythemia; Prefibrotic primary myelofibrosis; Primary myelofibrosis; GATA1

MeSH Terms

Alleles
Biopsy
Bone Marrow
Classification
Cohort Studies
Fibrosis
Follow-Up Studies
Humans
Medical Records
Polycythemia Vera
Primary Myelofibrosis
Thrombocythemia, Essential
World Health Organization

Figure

  • Fig. 1 Representative images of GATA1 immunoexpression in bone marrow biopsy samples according to the intensity of the reaction (×400): (A) negative, (B) weak, (C) moderate, and (D) strong. Megakaryocytes (arrows) are identified by CD61-stained (pink-colored) cytoplasm. GATA1-stained nuclei of megakaryocytes colored light to dark brown depending on the immunointensity. GATA1-stained nuclei are also seen in erythroid cells (arrowhead) without the CD61-positive cytoplasm.

  • Fig. 2 Distribution of GATA1 expression according to disease groups (P=0.004).Abbreviations: BHD, benign hematologic disease; CML, chronic myeloid leukemia; ET, essential thrombocythemia; LWOB, lymphoma without bone marrow involvement; PMF, primary myelofibrosis; prePMF, prefibrotic primary myelofibrosis; PV, polycythemia vera.

  • Fig. 3 Serial analysis of GATA1 expression, the allele burden of JAK2 V617F, and clinical events in patients with polycythemia vera or essential thrombocythemia.*CALR type 1 mutated; †CALR type 2 mutated; ‡Triple negative.Abbreviations: ET, essential thrombocythemia; F/U, follow-up; mo, month; MF, myelofibrosis; NT, not tested; PV, polycythemia vera.

  • Fig. 4 Serial analysis of GATA1 expression, the allele burden of JAK2 V617F, and clinical events in patients with prefibrotic primary myelofibrosis or primary myelofibrosis.*CALR type 1 mutated; †CALR type 2 mutated; ‡Triple negative; §Mutations not tested; ∥JAK2 V617F mutated. Allele burden quantification was not performed.Abbreviations: AML, transformation to acute myeloid leukemia; F/U, follow-up; mo, month; MF, myelofibrosis; NT, not tested; PMF, primary myelofibrosis; prePMF, prefibrotic primary myelofibrosis.


Reference

1. Arber DA, Orazi A, Hasserjian R, Thiele J, Borowitz MJ, Le Beau MM, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127:2391–2405. PMID: 27069254.
2. Levine RL. Another piece of the myeloproliferative neoplasms puzzle. N Engl J Med. 2013; 369:2451–2452. PMID: 24325357.
3. Vannucchi AM, Guglielmelli P, Tefferi A. Advances in understanding and management of myeloproliferative neoplasms. CA Cancer J Clin. 2009; 59:171–191. PMID: 19369682.
4. Cervantes F, Passamonti F, Barosi G. Life expectancy and prognostic factors in the classic BCR/ABL-negative myeloproliferative disorders. Leukemia. 2008; 22:905–914. PMID: 18385755.
5. Tefferi A, Huang J, Schwager S, Li CY, Wu W, Pardanani A, et al. Validation and comparison of contemporary prognostic models in primary myelofibrosis: analysis based on 334 patients from a single institution. Cancer. 2007; 109:2083–2088. PMID: 17407134.
6. Tefferi A, Lasho TL, Finke CM, Knudson RA, Ketterling R, Hanson CH, et al. CALR vs JAK2 vs MPL-mutated or triple-negative myelofibrosis: clinical, cytogenetic and molecular comparisons. Leukemia. 2014; 28:1472–1477. PMID: 24402162.
7. Tefferi A, Pardanani A. Myeloproliferative neoplasms: A contemporary review. JAMA Oncol. 2015; 1:97–105. PMID: 26182311.
8. Barbui T, Thiele J, Vannucchi AM, Tefferi A. Problems and pitfalls regarding WHO-defined diagnosis of early/prefibrotic primary myelofibrosis versus essential thrombocythemia. Leukemia. 2013; 27:1953–1958. PMID: 23467025.
9. Buhr T, Hebeda K, Kaloutsi V, Porwit A, Van der Walt J, Kreipe H. European Bone Marrow Working Group trial on reproducibility of World Health Organization criteria to discriminate essential thrombocythemia from prefibrotic primary myelofibrosis. Haematologica. 2012; 97:360–365. PMID: 22058215.
10. Barosi G. Essential thrombocythemia vs. early/prefibrotic myelofibrosis: why does it matter. Best Pract Res Clin Haematol. 2014; 27:129–140. PMID: 25189724.
11. Gisslinger H, Jeryczynski G, Gisslinger B, Wolfler A, Burgstaller S, Buxhofer-Ausch V, et al. Clinical impact of bone marrow morphology for the diagnosis of essential thrombocythemia: comparison between the BCSH and the WHO criteria. Leukemia. 2016; 30:1126–1132. PMID: 26710883.
12. Barbui T, Thiele J, Passamonti F, Rumi E, Boveri E, Ruggeri M, et al. Survival and disease progression in essential thrombocythemia are significantly influenced by accurate morphologic diagnosis: an international study. J Clin Oncol. 2011; 29:3179–3184. PMID: 21747083.
13. Bjorkholm M, Hultcrantz M, Derolf AR. Leukemic transformation in myeloproliferative neoplasms: therapy-related or unrelated? Best Pract Res Clin Haematol. 2014; 27:141–153. PMID: 25189725.
14. Thiele J, Kvasnicka HM, Mullauer L, Buxhofer-Ausch V, Gisslinger B, Gisslinger H. Essential thrombocythemia versus early primary myelofibrosis: a multicenter study to validate the WHO classification. Blood. 2011; 117:5710–5718. PMID: 21447832.
15. Barbui T, Thiele J, Vannucchi AM, Tefferi A. Rationale for revision and proposed changes of the WHO diagnostic criteria for polycythemia vera, essential thrombocythemia and primary myelofibrosis. Blood Cancer J. 2015; 5:e337. PMID: 26832847.
16. Shimizu R, Yamamoto M. GATA-related hematologic disorders. Exp Hematol. 2016; 44:696–705. PMID: 27235756.
17. Vannucchi AM, Pancrazzi A, Guglielmelli P, Di Lollo S, Bogani C, Baroni G, et al. Abnormalities of GATA-1 in megakaryocytes from patients with idiopathic myelofibrosis. Am J Pathol. 2005; 167:849–858. PMID: 16127162.
18. Bresnick EH, Katsumura KR, Lee HY, Johnson KD, Perkins AS. Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies. Nucleic Acids Res. 2012; 40:5819–5831. PMID: 22492510.
19. Garimella R, Kacena MA, Tague SE, Wang J, Horowitz MC, Anderson HC. Expression of bone morphogenetic proteins and their receptors in the bone marrow megakaryocytes of GATA-1(low) mice: a possible role in osteosclerosis. J Histochem Cytochem. 2007; 55:745–752. PMID: 17371937.
20. Rinaldi CR, Martinelli V, Rinaldi P, Ciancia R, del Vecchio L. GATA1 is overexpressed in patients with essential thrombocythemia and polycythemia vera but not in patients with primary myelofibrosis or chronic myelogenous leukemia. Leuk Lymphoma. 2008; 49:1416–1419. PMID: 18452096.
21. Jaffe ES. World Health Organization. Pathology and genetics of tumours of haematopoietic and lymphoid tissues. 1st ed. Lyon and Oxford: IARC Press; Oxford University Press (distributor);2001.
22. Swerdlow SH. International Agency for Research on Cancer. World Health Organization. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: International Agency for Research on Cancer;2008.
23. Ponce CC, de Lourdes FCM, Ihara SS, Silva MR. The relationship of the active and latent forms of TGF-beta1 with marrow fibrosis in essential thrombocythemia and primary myelofibrosis. Med Oncol. 2012; 29:2337–2344. PMID: 22200991.
24. Krajewska M, Krajewski S, Epstein JI, Shabaik A, Sauvageot J, Song K, et al. Immunohistochemical analysis of bcl-2, bax, bcl-X, and mcl-1 expression in prostate cancers. Am J Pathol. 1996; 148:1567–1576. PMID: 8623925.
25. Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369:2379–2390. PMID: 24325356.
26. Rotunno G, Mannarelli C, Guglielmelli P, Pacilli A, Pancrazzi A, Pieri L, et al. Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia. Blood. 2014; 123:1552–1555. PMID: 24371211.
27. Palandri F, Latagliata R, Polverelli N, Tieghi A, Crugnola M, Martino B, et al. Mutations and long-term outcome of 217 young patients with essential thrombocythemia or early primary myelofibrosis. Leukemia. 2015; 29:1344–1349. PMID: 25801912.
28. Edahiro Y, Morishita S, Takahashi K, Hironaka Y, Yahata Y, Sunami Y, et al. JAK2V617F mutation status and allele burden in classical Ph-negative myeloproliferative neoplasms in Japan. Int J Hematol. 2014; 99:625–634. PMID: 24677207.
29. Hussein K, Bock O, Theophile K, von Neuhoff N, Buhr T, Schlue J, et al. JAK2(V617F) allele burden discriminates essential thrombocythemia from a subset of prefibrotic-stage primary myelofibrosis. Exp Hematol. 2009; 37:1186–1193.e7. PMID: 19616600.
30. Park SH, Chi HS, Cho YU, Jang S, Park CJ. The allele burden of JAK2-V617F can aid in differential diagnosis of Philadelphia chromosome-negative myeloproliferative neoplasm. Blood Res. 2013; 48:128–132. PMID: 23826582.
31. Shirane S, Araki M, Morishita S, Edahiro Y, Sunami Y, Hironaka Y, et al. Consequences of the JAK2V617F allele burden for the prediction of transformation into myelofibrosis from polycythemia vera and essential thrombocythemia. Int J Hematol. 2015; 101:148–153. PMID: 25522845.
32. Yonal-Hindilerden I, Daglar-Aday A, Akadam-Teker B, Yilmaz C, Nalcaci M, Yavuz AS, et al. The burden of JAK2V617F mutated allele in Turkish patients with myeloproliferative neoplasms. J Clin Med Res. 2015; 7:161–170. PMID: 25584101.
33. Kiladjian JJ. The spectrum of JAK2-positive myeloproliferative neoplasms. Hematology Am Soc Hematol Educ Program. 2012; 2012:561–566. PMID: 23233635.
34. Larsen TS, Pallisgaard N, Moller MB, Hasselbalch HC. The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis--impact on disease phenotype. Eur J Haematol. 2007; 79:508–515. PMID: 17961178.
35. Vannucchi AM, Antonioli E, Guglielmelli P, Pardanani A, Tefferi A. Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia. 2008; 22:1299–1307. PMID: 18496562.
36. Vannucchi AM, Bianchi L, Paoletti F, Di Giacomo V, Migliaccio G, Migliaccio AR. Impaired GATA-1 expression and myelofibrosis in an animal model. Pathol Biol (Paris). 2004; 52:275–279. PMID: 15217713.
37. Brousseau M, Parot-Schinkel E, Moles MP, Boyer F, Hunault M, Rousselet MC. Practical application and clinical impact of the WHO histopathological criteria on bone marrow biopsy for the diagnosis of essential thrombocythemia versus prefibrotic primary myelofibrosis. Histopathology. 2010; 56:758–767. PMID: 20546341.
38. Florena AM, Tripodo C, Iannitto E, Porcasi R, Ingrao S, Franco V. Value of bone marrow biopsy in the diagnosis of essential thrombocythemia. Haematologica. 2004; 89:911–919. PMID: 15339673.
39. Shimizu R, Yamamoto M. Contribution of GATA1 dysfunction to multistep leukemogenesis. Cancer Sci. 2012; 103:2039–2044. PMID: 22937757.
40. Shimizu R, Kobayashi E, Engel JD, Yamamoto M. Induction of hyperproliferative fetal megakaryopoiesis by an N-terminally truncated GATA1 mutant. Genes Cells. 2009; 14:1119–1131. PMID: 19682090.
Full Text Links
  • ALM
Actions
Cited
CITED
export Copy
Close
Share
  • Twitter
  • Facebook
Similar articles
Copyright © 2024 by Korean Association of Medical Journal Editors. All rights reserved.     E-mail: koreamed@kamje.or.kr