Conventional cytogenetics in myelofibrosis: literature review and discussion

Abstract

Myelofibrosis (MF) is a clonal hematopoietic stem cell disorder currently classified as a myeloproliferative neoplasm (MPN) (1). MF presents either de novo [primary MF (PMF)] or in the setting of either polycythemia vera (post-PV MF) or essential thrombocythemia (post-ET MF) (2). Clinical features include anemia that is often transfusion-requiring, marked splenomegaly that sometimes necessitates therapeutic splenectomy, constitutional symptoms that are often accompanied by cachexia, leukoerythroblastic blood smear, bone marrow fibrosis and extramedullary hematopoiesis. Median survival of PMF is approximately 69 months and causes of death include leukemic transformation and infection (3). Current therapy for MF includes allogeneic stem cell transplantation usually considered for transplant-eligible patients with high-risk disease. Drug therapy has not been shown to modify the natural history of the disease but alleviates anemia or splenomegaly in approximately 20% of patients (4).The primary disease-causing mutation(s) in MF is unknown. In 2005, a Janus kinase 2 (JAK2) gain-of-function mutation (JAK2V617F) was described in PV, . JAK2V617F is present in approximately 97% of patients with PV and 50% of those with either ET or PMF. In 2006 and 2007, additional JAK2 and MPL mutations were described in approximately 3% of patients with PV (JAK2 exon 12 mutations) and 5-10% of those with ET or PMF (MPLW515L ⁄ K and others) (5-10). These mutations occur at a primitive stem cell level but their precise pathogenetic contribution is still unclear. Diagnostic utility of JAK and MPL mutations in MPN has now been well established and their value as AbstractThe clinical phenotype of myelofibrosis (MF) is recognized either de novo (primary) or in the setting of polycythemia vera (post-PV) or essential thrombocythemia (post-ET). Approximately one-third of patients with primary MF (PMF) present with cytogenetic abnormalities; the most frequent are del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q. Other less frequent lesions include )7 ⁄ del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3). In general, cytogenetic abnormalities are qualitatively similar among PMF, post-ET MF and post-PV MF although their individual frequencies may differ. Based on prognostic effect, cytogenetic findings in MF are classified as either 'favorable' or 'unfavorable'. The former include normal karyotype or isolated del(20q) or del(13q) and the latter all other abnormalities. Unfavorable cytogenetic profile in both PMF and post-PV ⁄ ET MF confers an independent adverse effect on survival; it is also associated with higher JAK2V617F mutational frequency. In addition to their prognostic value, cytogenetic studies in MF ensure diagnostic exclusion of other myeloid neoplasms that are sometimes associated with bone marrow fibrosis (e.g. BCR-ABL1-positive or PDGFRBrearranged) and also assist in specific treatment selection (e.g. lenalidomide therapy is active in MF associated with del(5q).

Development of monocytosis in patients with primary myelofibrosis indicates an accelerated phase of the disease

“…In our cases, although the frequency of cytogenetic abnormalities was higher (57%) than that expected in primary myelofibrosis (30%), 1,21 there was no association between the development of monocytosis and the type or occurrence of cytogenetic abnormalities. Thus, in our series evidence of a parallel cytogenetic progression was not detected.…”

New Сytogenetic Approaches in Patients with Primary Myelofibrosis

“…1), прогностическая значимость которых при ПМФ была показана неодно-кратно [30][31][32][33][34][35]. Согласно опубликованным данным, успешные цитогенетические исследования костного мозга до последнего времени удавалось проводить лишь у 15-30 % пациентов [16][17][18][19][20][21][22][23]. Результаты работы удалось существенно улучшить недавно, когда для цито-генетического анализа стали использовать 48-часовые нестимулированные культуры крови [24].…”

“…Основной акцент делался на повреждения хромосом 3, 1 и 13 [9,13]. Масштабные цитогенетические исследо-вания при ПМФ были выполнены относительно недавно [16][17][18][19][20][21][22][23]. Они показали, что у этих больных чаще других встречаются делеции длинного плеча хромосом 20, 13 и 11, а также дупликации длинного плеча хромосомы 1.…”

“…1, заимствованной из обзора K. Hussein и соавт. [18] и дополненной только что опубликованными данными ки-тайских исследователей [22].…”

Paediatric Idiopathic Myelofibrosis

“…However, unlike adult myelofibrosis where JAK2V617F or MPLW515 K/L mutations are present in about 50 % cases, absence of these mutations has been described in pediatric cases, suggesting a different clonal change in pediatric myelofibrosis. This hypothesis is also strengthened by presence of different cytogenetic abnormalities like trisomy 21 in pediatric myelofibrosis [1], versus trisomies in chromosomes 8 or 9, deletions in the long arm of chromosomes 20 or 13, and abnormalities in chromosome 1 in adults [7].…”