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Erythroid and Megakaryocytic Transformation Oncogene (2007) 26, 6803–6815 & 2007 Nature Publishing Group All rights reserved 0950-9232/07 $30.00 www.nature.com/onc REVIEW Erythroid and megakaryocytic transformation A Wickrema1 and JD Crispino2 1Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA and 2Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA Red blood cells and megakaryocytes arise from a common Accumulated evidence mostly from studies with precursor, the megakaryocyte-erythroid progenitor and mouse models and human primary cells suggests that share many regulators including the transcription factors cellular expansion and differentiation occur concur- GATA-1 and GFI-1B and signaling molecules such as JAK2 rently until the late stages of erythroid differentiation and STAT5. These lineages also share the distinction (polychromatic/orthochromatic) at which point the cells of being associated with rare, but aggressive malignancies exit the cell cycle and undergo terminal maturation that have very poor prognoses. In this review, we (Wickrema et al., 1992; Ney and D’Andrea, 2000; will briefly summarize features of normal development of Koury et al., 2002). A disruption of the balance between red blood cells and megakaryocytes and also highlight erythroid cell expansion and differentiation results in events that lead to their leukemic transformation. It is either myeloproliferative disorders (MPDs) such as clear that much more work needs to be done to improve our polycythemia vera, myelodysplastic syndrome, or rarely understanding of the unique biology of these leukemias in erythroleukemia. Furthermore, some patients initially and to pave the way for novel targeted therapeutics. diagnosed with MPDs ultimately progress to erythro- Oncogene (2007) 26, 6803–6815; doi:10.1038/sj.onc.1210763 leukemia. In this first part of the review, we will highlight key factors that regulate the erythroid Keywords: AMKL; erythroleukemia; myeloproliferative differentiation program and their contribution to diseases; GATA1; RUNX1; Fli-1; Friend virus erythroleukemia. Clinical characteristics of erythroleukemia Erythroleukemia is a relatively rare disease in humans Normal and malignant erythropoiesis accounting for approximately 5% of all acute myeloid leukemia (AML). The disease is more prevalent in Development of erythroid cells males, and 50% of all cases are considered therapy- Commitment of hematopoietic stem cells/early progeni- related leukemias due to prior exposure to chemother- tors to the erythroid lineage takes place within the bone apy or immunosuppressive agents. In addition, some marrow microenvironment under the influence of multi- cases occur as end-stage transformation of myelodys- ple regulatory factors. Pleotrophic and lineage-specific plastic syndrome. The disease has a bimodal distribution cytokines play a key role in the commitment and with a small peak in patients under the age of 20 and an differentiation of erythroid cells (Figure 1). In addition, increasing incidence in patients over the age of 70. transcription factors, the bone marrow microenviron- Patients typically present with fatigue and anemia and ment and numerous signaling proteins also play a vital occasional hepato- or splenomegaly. The large majority function in guiding and promoting expansion and of patients have cytogenetic abnormalities in the bone differentiation of erythroid progenitors. During the past marrow, many of them associated with an adverse two decades, especially since the discovery of erythro- prognosis (such as deletions of chromosome 5 or 7) poietin in mid-1980s, it has been possible to system- (Michiels et al., 1997; Park et al., 2002). Unlike chronic atically study the contribution of various transcription myelogenous leukemia, there is no single characteristic factors and signaling proteins in the expansion and cytogenetic abnormality associated with erythroleuke- differentiation of erythroid progenitors into mature mia. The diagnosis is established by examination of the circulating erythroid cells (Cantor and Orkin, 2002; peripheral blood and bone marrow, which is hypercel- Koury et al., 2002). These studies have greatly lular and commonly displays trilineage dysplasia. Two contributed to our understanding of regulatory factors subtypes of acute erythroleukemia are recognized in the responsible for both erythroid cell expansion as well as current World Health Organization classification: ery- differentiation. throleukemia (erythroid/myeloid), also commonly named M6a, is defined by the presence in the bone marrow of >50% erythroid precursors in the entire Correspondence: Professor JD Crispino, Division of Hematology/ Oncology, Northwestern University, 303 E. Superior Street, Lurie nucleated cell population and >20% myeloblasts in the 5-113, Chicago, IL 60611, USA. non-erythroid population, (that is, the myeloblasts are E-mail: [email protected] calculated as a percentage of the non-erythroid bone Erythroid and megakaryocytic malignancies A Wickrema and JD Crispino 6804 Figure 1 A model for human erythroid cell development and potential factors influencing the transformation into erythroleukemia. The scheme outlines the stages of maturation and cytokine requirements at each stage of erythroid differentiation in addition to temporal expression pattern of transcription factors during differentiation. Expression pattern of cytokine receptors (in parentheses) and stage-specific activation of signal transduction proteins are also depicted in the scheme. Morphological changes in size, shape and color (due to hemoglobin) are indicated as part of the differentiation program. Aberrant expression of transcription factors and activation of signaling proteins in human and/or murine erythroleukemia are shown in bold italics (red). marrow cells). The second subtype, pure erythroleuke- Transformation of human erythroid cells mia, also known as M6b, represents a neoplastic Transformation of normal erythroid progenitors to proliferation of immature cells committed exclusively leukemia cells is a multistep process that occurs over a to the erythroid lineage (>80% of marrow cells) with no long period of time. It is characterized by expansion of evidence of a significant myeloid component (Jaffe, erythroid progenitors at the expense of terminal differ- 2001). Cytochemical stains sometimes show aberrant entiation and can occur at any of the distinct stages of periodic acid Schiff (PAS) positivity in erythroid erythroid maturation. For example, minimally differenti- precursors, while Prussian blue stains demonstrate ated erythroleukemia includes cells that are mostly at increased iron stores and sometimes ringed sideroblasts. early stages after commitment to erythroid lineage Immunophenotyping gives variable results, however, the (burst-forming unit erythroid, BFU-E). Such immature classic erythroid markers glycophorin A and CD71 erythroleukemia cells exhibit an HLADRÀ/CD36 þ (transferrin receptor) are useful in classification of phenotype. On the other hand, erythroleukemia ambiguous cases. affecting the late stages of maturation (colony-forming Treatment for patients with erythroleukemia is similar unit erythroid, CFU-E), exhibit more mature morpho- to that of other AML patients, but their outcome tends logy and are generally positive for glycophorin A (Park to be poor, with the majority of patients relapsing after et al., 2002). Although the molecular mechanisms an initial response. Allogeneic bone marrow transplan- underlying the transformation of erythroid cells into tation is considered a curative treatment, although its erythroleukemia in humans are not well understood, cell use is limited by comorbidities in elderly patients and by lines generated from patient samples have been quite lack of suitable donors. Erythroleukemia is a rare useful in characterizing some of the key biochemical and disease, and as a result relatively few clinical samples cellular characteristics of this malignancy. Approxi- have been available for research. The ability to study mately 21 human erythroleukemia cell lines have been primary erythroleukemia in vitro has been further utilized in studies to understand the proliferation and hampered by the fact that most erythroleukemic differentiation program of the erythroid lineage (Drexler patients have their myeloid compartment also affected et al., 2004). The best-known one is the K562 cell line, by leukemia. Therefore, much of the research has been which has been extensively used over the last 25 years to performed using mouse models or human cell lines. study the ‘normal’ erythroid differentiation program, Oncogene Erythroid and megakaryocytic malignancies A Wickrema and JD Crispino 6805 but which originated from a patient with chronic The differences in the manifestation of the disease in myelogenous leukemia in blasts crisis (and thus ex- these two strains are due to differences in a few amino presses the BCR/ABL fusion protein). These available acids within the gp55 protein (Chung et al., 1989; Fang erythroleukemia cell lines exhibit a wide range of et al., 1998). Mice infected with SFFV anemia strain functional characteristics such as variable cytokine exhibit clonal expansion with terminal differentiation in requirements and differing abilities to differentiate in the presence of Epo. During the initial stage of infection, culture with or without differentiation agents. There- erythroid progenitors are found mostly at the colony- fore, despite their common use for this purpose, these forming unit erythroid stage
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