Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome–negative myeloproliferative neoplasms

Thoennissen, Nils H.; Krug, Utz; Lee, Dhong Hyun Tony; Kawamata, Norihiko; Iwanski, Gabriela B.; Lasho, Terra L.; Weiss, Tamara; Nowak, Daniel; Koren‐Michowitz, Maya; Kato, Motohiro; Sanada, Masashi; Shih, Lee Yung; Nagler, Arnon; Raynaud, Sophie; Müller‐Tidow, Carsten; Mesa, Ruben A.; Haferlach, Torsten; Gilliland, D. Gary; Tefferi, Ayalew; Ogawa, Seishi; Koeffler, H. Phillip

doi:10.1182/blood-2009-07-235119

Cited by 115 publications

(120 citation statements)

References 39 publications

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“…Although early cytogenetic studies and polymorphic marker analyses clearly pointed to the presence of a tumour suppressor gene on 7q22.1, the implicated gene was not rapidly identified. CUX1 and a few other genes were consistently present within the smallest deleted region, but no mutation was found in the remaining allele of any of these genes [7][8][9][10] . These results eventually led to the idea that inactivation of the tumour suppressor on 7q22.1 may not conform to the Knudson two-hit model.…”

Section: The Knudson Two-hit Modelmentioning

confidence: 95%

“…Although genetic evidence indicates that one CUX1 allele remains intact in all cases of LOH or inactivating point mutations, two patients with post-MPN AML harboured a homozygous deletion spanning CUX1 (REFS 6,10), and another patient with chronic myelomonocytic leukaemia had heterozygous nonsense CUX1 mutations 11 . It is therefore possible that in rare cases, CUX1 is inactivated like a classical tumour suppressor gene.…”

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

“…In uterine leiomyomas, a positional cloning approach revealed two cases of genomic rearrangements with breakpoints predicted to inactivate one CUX1 allele 3 . High-resolution single-nucleotide polymorphism (SNP) microarray analysis indicated that progression of Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) to AML was associated with frequent LOH of the 7q22.1 chromosomal region 6,10 . In one study, mapping of the commonly deleted region identified CUX1 as the single target gene 6 .…”

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

“…Recent genetic mapping and expression analyses pointed to CUX1 as the tumour suppressor that is the target of loss-of-heterozygosity (LOH) on chromosome 7q22.1 . In cancers with CUX1 LOH, no mutations have been found in the remaining allele [7][8][9][10] and, in tested cases, CUX1 was expressed, albeit at a reduced level 4,5,11 . However, inactivating point mutations were shown in 1-5% of cancers in which the two CUX1 alleles are present 11 (FIG.…”

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confidence: 90%

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CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

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Section: The Knudson Two-hit Modelmentioning

confidence: 95%

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

Section: The Knudson Two-hit Modelmentioning

confidence: 99%

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confidence: 90%

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CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

2014

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“…In fact, irrespective of the JAK2 (V617F) mutational status, additional oncogenic events likely participate in leukemic transformation. 37 This is shown by the high rate of patients showing a complex karyotype, 38,39 and by the several additionally altered regions identified with SNP-chip analysis 40 at leukemic transformation. Our results parallel those obtained in primary MF, 41,42 in which a relationship between JAK2 mutant allele burden and leukemia was not evident.…”

Section: Tablementioning

confidence: 99%

A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications

et al. 2010

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Somatic Mutations in Polycythaemia Vera and Other Philadelphia Chromosome Negative Myeloproliferative Neoplasms

Gondek

Spivak

2012

Encyclopedia of Life Sciences

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The just another kinase (JAK) family kinases function as the cognate tyrosine kinases for Type I/II cytokine receptors that lack intrinsic kinase domains. Perhaps the most important is JAK2, which is also a chaperone for the erythropoietin and thrombopoietin receptors as well as the kinase utilised alone or with other JAK kinases in the majority of cytokine receptors. JAK2 can be considered an oncogene because it is responsible for promoting cell proliferation and preventing apoptosis and its constitutive activation causes acute and chronic leukaemias and lymphomas. The most common JAK2‐activating mutation, V617F, is responsible for the clinical phenotype of polycythaemia vera and that of approximately 50% of cases of essential thrombocytosis and primary myelofibrosis. In recent studies of JAK2 inhibitors in primary myelofibrosis there was amelioration of clinical symptoms and a reduction in splenomegaly, supporting an important role of JAK2 in the myeloproliferative phenotype and identifying a new treatment for these disorders. Key Concepts: The Janus kinase family has a crucial role in hematopoietic and immune cell function. JAK2 V617F‐activating mutation is the most frequent genetic alteration in polycythaemia vera, essential thrombocytosis and primary meylofibrosis. JAK2 V617F has oncogenic properties and is responsible for uncontrolled cell proliferation, inhibition of apoptosis, genetic instability via induction of proto‐oncogenes, reactive oxygen species and promotion of mitotic recombination. JAK2 exon 12 mutations are frequent in JAK2 V617‐negative polycythaemia vera patients. JAK2 mutation alone cannot entirely explain the disease phenotype in the myeloproliferative disorders and genetic predisposition seems to play an important role in both the acquisition of these mutations and disease pathogenesis. The role of JAK2 V617F mutation as a marker for disease prognosis is unresolved. JAK2 inhibitors improve constitutional symptoms and reduce splenomegaly in primary myelofibrosis patients.

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Prevalence and prognostic impact of allelic imbalances associated with leukemic transformation of Philadelphia chromosome–negative myeloproliferative neoplasms

Cited by 115 publications

References 39 publications

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

CUX1, a haploinsufficient tumour suppressor gene overexpressed in advanced cancers

A prospective study of 338 patients with polycythemia vera: the impact of JAK2 (V617F) allele burden and leukocytosis on fibrotic or leukemic disease transformation and vascular complications

Somatic Mutations in Polycythaemia Vera and Other Philadelphia Chromosome Negative Myeloproliferative Neoplasms

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