<i>JAK2</i> V617F Mutation is uncommon in chronic myelomonocytic leukaemia

Johan, Muhammad Farid; Goodeve, Anne; Bowen, David; Frew, Marion E.; Reilly, John T.

doi:10.1111/j.1365-2141.2005.05719.x

Cited by 28 publications

(12 citation statements)

References 9 publications

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“…[2][3][4][5][6] Subsequent studies in related diseases, including MDS, showed that in typical MDS and CMML, 8,[12][13][14][15] only a low prevalence of JAK2 V617F can be found. We have hypothesized that JAK2 V617F mutation may be present in patients who show features common to typical CMPD and MDS, such as those with MDS/MPD overlap subentities, and we focused our study on this group of patients.…”

Section: Resultsmentioning

confidence: 99%

“…[12][13][14] The relatively close association of the JAK2 V617F mutation with certain CMPD could provide insight into how the MDS/MPD entities are related to either MDS or CMPD. When a large cohort of patients with CMML was examined for the presence of the JAK2 V617F mutation, this defect was found only in a small proportion of patients, 12,13,15 suggesting that CMML is less biologically related to CMPD.…”

Section: Introductionmentioning

confidence: 99%

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Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation

Szpurka

Tiu

Murugesan

et al. 2006

Blood

185

123

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JAK2 V617F mutation recently was identified as a pathogenic factor in typical chronic myeloproliferative diseases (CMPD). Some forms of myelodysplastic syndromes (MDS) show a significant overlap with CMPD (classified as MDS/MPD), but the diagnostic assignment may be challenging. We studied blood or bone marrow from 270 patients with MDS, MDS/MPD, and CMPD for the presence of JAK2 V617F mutation using polymerase chain reaction, sequencing, and melting curve analysis. The detection rate of JAK2 V617F mutants for polycythemia vera, chronic idiopathic myelofibrosis, and essential thrombocythemia (n ‫؍‬ 103) was similar to the previously reported results. In typical forms of MDS (n ‫؍‬ 89) JAK2 V617F mutation was very rare (n ‫؍‬ 2). However, a higher prevalence of this mutation was found in patients with MDS/MPD-U (9 of 35). Within this group, most of the patients harboring JAK2 V617F mutation showed features consistent with the provisional MDS/MPD-U entity refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T). Among 9 RARS-T patients, 6 showed the presence of JAK2 V617F mutation, and in 1 patient without mutation, aberrant, positive phospho-STAT5 staining was seen that is typically present in association with JAK2 V617F mutation. In summary, we found that RARS-T reveals a high frequency of JAK2 V617F mutation and likely constitutes another JAK2 mutation-associated form of

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation

Szpurka

Tiu

Murugesan

et al. 2006

Blood

185

123

View full text Add to dashboard Cite

show abstract

“…In the Philadelphia chromosome-negative chronic myeloproliferative disorders, the JAK2 V617F mutation is thought to contribute to the marrow myeloproliferation by its induction of growth factor independence. 27 In view of the lack of specific disease marker, the diagnosis of CMML is still largely based on clinicalmorphologic observations. The hybrid nature of CMML with features of both a myelodysplastic syndrome and a myeloproliferative disorder creates both diagnostic difficulties and difficulties in the prediction of clinical behavior.…”

Section: Cytogenetic Resultsmentioning

confidence: 99%

Chronic myelomonocytic leukemia: the role of bone marrow biopsy immunohistology

et al. 2006

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The World Health Organization criteria for diagnosing chronic myelomonocytic leukemia (CMML) are largely based on findings observed in the peripheral blood and bone marrow aspirate. A specific diagnostic role for the bone marrow biopsy has not been adequately explored. We examined whether bone marrow biopsy supplemented by immunohistochemistry may be helpful in distinguishing CMML from cases of chronic myelogenous leukemia and atypical chronic myeloid leukemia (aCML). We immunostained 25 cases of CMML with paraffin reactive antibodies which included CD68 (KP1), CD68R (PG-M1), and CD163, and compared the results with those observed in six cases of chronic myelogenous leukemia and in three cases of atypical CML. In addition, we examined whether CD34 immunohistochemistry could be useful in separating cases of CMML with less than 10% blasts (type-1) from cases of CMML with blasts accounting for 10-19% (type-2), and cases of CMML in acute transformation to acute myeloid leukemia (blastsZ20%). The presence of nodules of plasmacytoid monocytes was investigated by CD123 staining. CD42b was used to highlight abnormal megakaryocytes. Our results demonstrate significant differences between the groups. CD34 analysis allowed separating CMML type-1 from type-2 and the former from CMML in acute transformation. CD123-positive plasmacytoid monocyte nodules were found only in CMML and not in the other two disease groups. Overlap between CMML and the other two groups were observed with CD68 immunostaining. CD68R was more restricted to bone marrow macrophages and monocytes than CD68, but the differences between CMML and chronic myelogenous leukemia or atypical CML were still not significant. Although CD42b immunostaining facilitated the detection of dwarf megakaryocytes often present in CMML, the distinction between those and the small forms seen in chronic myelogenous leukemia was still problematic.

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“…JAK2V617F represents the major molecular lesion in patients with BCR/ABL-negative myeloproliferative disorders (MPD). Subsequent large-scale screenings of patients with various blood disorders also found the JAK2V617F mutation in a relatively low percentage of cases of chronic myelomonocytic leukemia, myelodysplastic syndrome, and acute myeloid leukemia (12)(13)(14)(15)(16). Further studies have also identified new mutations adjacent to the JH2 domain of JAK2 in PV patients (17), and additional mutations in the JH2 domain of JAK2 and JAK3 in established acute megakaryoblastic leukemia cell lines (18,19).…”

mentioning

confidence: 99%

Dimerization by a Cytokine Receptor Is Necessary for Constitutive Activation of JAK2V617F

Lü

Huang

Lodish

2008

Journal of Biological Chemistry

118

125

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The majority of the BCR-ABL-negative myeloproliferative disorders express the mutant JAK2, JAK2V617F. Previously we showed that constitutive activation of this oncogenic JAK2 mutant in Ba/F3 or 32D cells requires coexpression of a cognate homodimeric cytokine receptor, such as the EpoR. However, overexpression of JAK2V617F in Ba/F3 cells renders them cytokine-independent for growth in the absence of an exogenous cytokine receptor. Here, we demonstrated that JAK2V617F domains required for receptor association are essential for cytokine-independent growth by overexpressed JAK2V617F, suggesting JAK2V617F is binding to an unknown endogenous cytokine receptor(s) for its activation. We further showed that disruption of EpoR dimerization by coexpressing a truncated EpoR disrupted JAK2V617F-mediated transformation, indicating that EpoR dimerization plays an essential role in the activation of JAK2V617F. Interestingly, coexpression of JAK2V617F with EpoR mutants that retain JAK2 binding but are defective in mediating Epo-dependent JAK2 activation due to mutations in a conserved juxtamembrane motif does lead to cytokine-independent activation of JAK2V617F. Overall, these findings confirm that JAK2V617F requires binding to a dimerized cytokine receptor for its activation, and that the key EpoR juxtamembrane regulatory motif essential for Epo-dependent JAK2 activation is not essential for the activation of JAK2V617F. The structure of the activated JAK2V617F is thus likely to be different from that of the activated wild-type JAK2, raising the possibility of developing a specifically targeted therapy for myeloproliferative disorders.

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JAK2 V617F Mutation is uncommon in chronic myelomonocytic leukaemia

Cited by 28 publications

References 9 publications

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation

Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation

Chronic myelomonocytic leukemia: the role of bone marrow biopsy immunohistology

Dimerization by a Cytokine Receptor Is Necessary for Constitutive Activation of JAK2V617F

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