Partial trisomy 1q in idiopathic myelofibrosis

2008

Leukemia

The frequency of cytogenetic abnormalities in the Philadelphianegative myeloproliferative neoplasms (MPNs) varies from approximately 30% in primary myelofibrosis (PMF) to less than 5% in essential thrombocytosis (ET). The spectrum of aberrations is heterogeneous, ranging from gains and losses of genetic material to structural changes including unbalanced translocations. However, no specific abnormality has been identified to date. Nevertheless, such investigations can provide evidence of clonality and, as a result, cytogenetic findings have been included in the WHO diagnostic criteria for this group of diseases. The aim of the current review is to discuss the pathogenetic insight and prognostic information that standard, as well as molecular cytogenetic analysis has provided. A brief overview is given of the cytogenetic findings in the individual diseases, followed by a more detailed discussion of the possible pathogenetic consequences of specific abnormalities and their impact on prognosis.

Section: Chromosomementioning

confidence: 99%

Pathogenetic insight and prognostic information from standard and molecular cytogenetic studies in the BCR-ABL-negative myeloproliferative neoplasms (MPNs)

2008

Leukemia

“…These rearrangements follow a definite non-random pattern and, although the whole of 1q may be involved, always appear to include the specific segment, 1q23–1q32 [57, 58, 59]. Duplicated 1q has been found at all stages of disease, including at diagnosis [34].…”

Section: Cytogenetic Analysismentioning

confidence: 99%

Cytogenetic and Molecular Genetic Aspects of Idiopathic Myelofibrosis

2002

Acta Haematol

Idiopathic myelofibrosis is a chronic myeloproliferative disorder in which the characteristic fibroblast proliferation is thought to be a secondary phenomenon resulting from the inappropriate release of megakaryocyte- and/or monocyte-derived growth factors, including PDGF, TGF-β, bFGF and calmodulin. In contrast, the haematopoietic cells are clonal, although the underlying pathogenetic mechanisms remain essentially unknown. Cytogenetic studies have highlighted that 13q–, 20q–, +8 and abnormalities of chromosomes 1, 7 and 9 constitute more than 80% of the chromosomal changes. A third of idiopathic myelofibrosis cases have abnormal karyotypes at diagnosis, a figure that increases if follow-up analyses are performed. Evolution to more complex karyotypes may accompany clinical progression, with abnormalities increasing to around 90% following acute leukaemic transformation. Cytogenetic abnormalities have been associated with prognosis and to a lack of treatment response to androgens. Oncogene mutations are rare and include point mutations in N-RAS, c-KIT and TP53.

“…The candidate gene remains unknown, although it is possible that more than one gene is involved since Macdonald et al [31] provided evidence for the involvement of a novel gene located at 13q12. Amplifications of 1q follow a non-random pattern and, although the whole of 1q may be involved, always appear to include the specific segment, 1q23-1q32 [32]. The inability to identify common breakpoints, or a preferential translocation site, suggests that an increase in gene(s) copy number on 1q is the pathogenetically important mechanism.…”

Section: Clonalitymentioning

confidence: 99%

Idiopathic myelofibrosis: pathogenesis to treatment

2006

Hematological Oncology

Idiopathic myelofibrosis (IMF) is the least common of the chronic myeloproliferative disorders and carries the worst prognosis with a median survival of 4 years. It is a clonal haematopoietic stem-cell disorder and, although the pathogenesis remains unclear, approximately 50% of cases are known to possess an activating JAK2 V617F mutation. In contrast, the characteristic stromal proliferation is a reactive, or secondary, event that results from the aberrant release of a variety of growth factors from megakaryocytes and monocytes. Treatment for most cases is supportive, although androgens, recombinant erythropoietin, steroids and thalidomide are effective modalities for the amelioration of anaemia. Myelosuppression, splenectomy and irradiation are valuable therapeutic modalities for specific clinical situations. Prognostic scores are available to aid the identification of cases for whom bone marrow transplantation should be considered. Recently, the use of reduced intensity conditioning has resulted in prolonged survival and lower transplant-related mortality. This review summarises the recent advances in the disease's pathogenesis and discusses the role of the various therapeutic options.