Acquired uniparental disomy of chromosome 9p is a frequent stem cell defect in polycythemia vera

Královics, Róbert; Guan, Yongli; Prchal, Josef T.

doi:10.1016/s0301-472x(01)00789-5

Cited by 275 publications

(214 citation statements)

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“…Among the most frequent are 9pUPD, numerical aberrations of chromosomes 1, 8 and 9, deletions of chromosomes 5q, 13q and 20q and frequent gains of 9p. 23,[64][65][66][67][68][69][70][71][72][73][74] Except 9pUPD, most of these cytogenetic aberrations are often present in other clonal myeloid disorders (myelodysplastic syndrome, CML and acute myeloid leukemia) and therefore, their role in the pathogenesis of hematological malignancies may be more universal. Tumor growth is considered to be a result of clonal evolution driven by sequential acquisition of somatic mutations.…”

Section: Cytogenetic Aberrations Of Mpn Are Shared With Other Clonal mentioning

confidence: 99%

“…UPD was first identified in MPN using a whole-genome microsatellite screening in which the short arm of chromosome 9 and the long arms of chromosomes 10 and 11 showed presence of loss of heterozygosity. 64 Further mapping of the relevant chromosomal region on 9p represented one of the approaches that led to the identification of JAK2-V617F mutation in MPN. 23 UPD is considered to be one of the genetic mechanisms involved in tumor suppressor inactivation as mutated or deleted alleles of tumor suppressors could become homozygous through mitotic recombination.…”

Section: Upd and Variability Of Mutational Burden In Mpnmentioning

confidence: 99%

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Genetic complexity of myeloproliferative neoplasms

Královics

2008

Leukemia

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Oncogenic mutations in JAK2 and MPL genes have recently been identified in myeloproliferative neoplasms (MPNs). In addition to these mutations, cytogenetic aberrations are frequently present at diagnosis but their role in the pathogenesis remains unclear. Two models of MPN pathogenesis have recently emerged based on either a single-hit or a multi-hit concept. The first model proposes that the acquisition of JAK2 mutations is the disease-initiating event, causing both the onset of disease phenotype and establishment of clonal hematopoiesis. The second model postulates the existence of 'pre-JAK2' mutations that establish clonal hematopoiesis before acquisition of JAK2 mutations and onset of disease phenotype. In this review, the two models have been critically evaluated in the context of the latest findings. At present, neither of the two models can be universally applied to all MPN patients due to their genetic heterogeneity. It is likely that the disease pathogenesis in some patients follows the first, and in other patients, the second model. Thus, the somatic mutations in MPN do not seem to be acquired in a predetermined order as seen in other malignancies, but occur randomly. Furthermore, the role of uniparental disomy in MPN and certain aspects of MPN therapy are discussed.

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Section: Cytogenetic Aberrations Of Mpn Are Shared With Other Clonal mentioning

confidence: 99%

Section: Upd and Variability Of Mutational Burden In Mpnmentioning

confidence: 99%

Genetic complexity of myeloproliferative neoplasms

Královics

2008

Leukemia

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“…Nevertheless, these and other studies suggested that gene(s) on 9p, rather than 9q, are crucial to the pathogenesis of PV. 93 In an attempt to clarify further the genomic regions that cause the PV phenotype, Kralovics et al 94 carried out a genome-wide microsatellite screen for LOH. Three genomic regions were identified on chromosomes 9p, 10q and 11q, with LOH of the 9p being found in a third of cases, making it the most frequent chromosomal lesion described at the time.…”

Section: Chromosomementioning

confidence: 99%

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

Reilly

2008

Leukemia

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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.

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“…88,89 These observations indicate that an additional event may precede JAK2V617F and may modify HSC biology to allow for clonal amplification. [90][91][92][93] Results from both mouse JAK2V617F þ bone marrow transplantation models and human JAK2V617F þ progenitor xenogeneic transplantation models indicate that JAK2V617F can initiate the skewed differentiation typical of PV but the events leading to the acquisition of this and other point mutations at the stem cell level are not clear at present. Molecular mutations that induce ET and MF in the 50% of patients who lack the JAK2V617F remain a subject of intensive investigation.…”

Section: Spotlightmentioning

confidence: 99%

“…99 This paper suggests that enhanced SPOTLIGHT JAK2 activation may activate hTERT expression and thereby, enhance survival and increase erythroid differentiation of stem cells. 99 Finally, MPD progression to myelofibrosis appears to be associated with an increase in JAK2V617F-expressing HSC 90 as well as overproduction of osteoprotegerin (OPG), which is an essential mediator of osteoblast production. 100 Osteoblasts form an essential component of the HSC niche in the bone marrow microenvironment and thus, increased osteoblast production may enhance the survival of miscreant MPD stem cells returning to the marrow (Figure 1).…”

Section: Bcr-abl-negative Mpd Survivalmentioning

confidence: 99%