Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9;22) (p24;q11.2) leading to <i>BCR‐JAK2</i> fusion

Lane, Steven; Fairbairn, David J.; McCarthy, Catherine; Nandini, Adayapalam; Perry-Keene, Joanna; Kennedy, Glen

doi:10.1111/j.1365-2141.2008.07164.x

Cited by 24 publications

(12 citation statements)

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“…Three additional studies report this translocation in leukemia patients. In contrast with the case presented here, the clinical diagnoses were found in atypical CML [9], [10] and AML [11]. Our finding indicates that this translocation is not restricted to the myeloid lineage.…”

Section: Discussioncontrasting

confidence: 99%

“…Sequence analysis revealed that this in-frame product corresponded to the expected BCR exon 1 region, which is usually found in the p190 BCR-ABL transcript fused to 90 bp corresponding to JAK2 exon 19 and flanked by the ABL reverse primer (ABL3) (Figure S1). In line with the results of recent cases of CML [9], [10] and AML [11], these data suggested the presence of a BCR-JAK2 fusion gene. RT-PCR assays were performed on the same samples (Figure 1B) with primers for BCR (BCR-B) and the stop codon of JAK2 (JAK2-Rv-T, see Table 1).…”

Section: Resultssupporting

confidence: 88%

“…The role of constitutively activated JAK2 or STAT5 in cellular transformation has been established [5]. Several fusion proteins involving the catalytic active JH1 domain of JAK2 have been reported to be associated with leukemia, as follows: 1) TEL-JAK2 was found in both pre-B-lineage and pre-T-lineage ALL and atypical chronic myelogenous leukemia (CML) [6], [7] 2) PCM1-JAK2 gene fusion resulting from t(8;9)(p22;p24) in eosinophilia-associated atypical CML, ALL, acute myeloid leukemia (AML), and T cell lymphoma [8], and 3) BCR-JAK2 gene fusion as the result of t(9;22)(p24;q11) was found in atypical CML [9], [10] and AML [11]. Other putative JAK2 translocations include SSBP2-JAK2 in pre-B ALL [12], PAX5 - and STRN3-JAK2 in childhood ALL [13] and SEC31A-JAK2 in classical non Hodgkin lymphoma [14].…”

Section: Introductionmentioning

confidence: 99%

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Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

et al. 2012

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Chromosomal translocations in tumors frequently produce fusion genes coding for chimeric proteins with a key role in oncogenesis. Recent reports described a BCR-JAK2 fusion gene in fatal chronic and acute myeloid leukemia, but the functional behavior of the chimeric protein remains uncharacterized. We used fluorescence in situ hybridization and reverse transcription polymerase chain reaction (RT-PCR) assays to describe a BCR-JAK2 fusion gene from a patient with acute lymphoblastic leukemia. The patient has been in complete remission for six years following treatment and autologous transplantation, and minimal residual disease was monitored by real-time RT-PCR. BCR-JAK2 codes for a protein containing the BCR oligomerization domain fused to the JAK2 tyrosine-kinase domain. In vitro analysis of transfected cells showed that BCR-JAK2 is located in the cytoplasm. Transduction of hematopoietic Ba/F3 cells with retroviral vectors carrying BCR-JAK2 induced IL-3-independent cell growth, constitutive activation of the chimeric protein as well as STAT5 phosphorylation and translocation to the nuclei, where Bcl-xL gene expression was elicited. Primary mouse progenitor cells transduced with BCR-JAK2 also showed increased proliferation and survival. Treatment with the JAK2 inhibitor TG101209 abrogated BCR-JAK2 and STAT5 phosphorylation, decreased Bcl-xL expression and triggered apoptosis of transformed Ba/F3 cells. Therefore, BCR-JAK2 is a novel tyrosine-kinase with transforming activity. It deregulates growth factor-dependent proliferation and cell survival, which can be abrogated by the TG101209 inhibitor. Moreover, transformed Ba/F3 cells developed tumors when injected subcutaneously into nude mice, thus proving the tumorigenic capacity of BCR-JAK2 in vivo . Together these findings suggest that adult and pediatric patients with BCR-ABL -negative leukemia and JAK2 overexpression may benefit from targeted therapies.

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Section: Discussioncontrasting

confidence: 99%

Section: Resultssupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

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Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

et al. 2012

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“…Although, the occurrence of such translocation led to fusion of BCR and JAK2, however, breakpoints of BCR in this patient were different with those of the patient in Germany (40). One year later, a study in Australia found t(9;22) (p24; q11.2), leading to BCR-JAK2 fusion in ACML patient with subcutaneous layer leukemia (41). Other translocations are also observed in JAK2 include SSBP2-JAK2 in pre-B ALL, PAX5-JAK2 and STRN3-JAK2 in children with ALL and SEC31-JAK2 in classical non-Hodgkin lymphoma (42)(43)(44).…”

Section: Bcr-jak2 Fusionmentioning

confidence: 56%

Myeloproliferative disorders and its associated mutations

et al. 2014

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Myeloproliferative Neoplasm (MPN) is a clonal disorder of hematopoietic stem cells (HSC). MPN is categorized as 8 subclasses, including chronic myeloid leukemia (CML), polycythemia vera (PV), essential thrombocytopenia (ET), primary myelofibrosis (PMF), systematic mastositosis (SM), chronic eosinophilic leukemia (CEL), chronic neutrophilic leukemia (CNL), and unclassified myelofibrosis disorders (UMPN). It usually occurs in 5th to 7th decade of life. However, CNL and ET have been also observed in children. A lot of mutations have been identified in these disorders which Jak2V617F is the most important mutation. Moreover, other than JAK2V617F, several somatic mutations have been reported in MPN patients. Such mutations include MPL, TET2, ASXL1, IDH1, IDH2, CBL, LNK, IKZF, and EZH2 in precursor stem cells. The role of mutations mentioned is not clear in pathogenesis of this disease. Therefore, in this study, mutations in different stages of myeloproliferative disorders have been reviewed.

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“…The PCM1 coiled motifs possibly serve as a dimerization motif to bring about constitutive activation of Jak2. Lastly, BCR-Jak2 fusions have been identified in patients with typical and atypical chronic myeloid leukemia [22,23••]. In each case, in situ hybridization revealed a t(9;22)(p24;q11.2) translocation in these patients as opposed to the typical t(9;22)(q34;q11.2) translocation.…”

Section: The Role Of Jak2 In Hematologic Malignanciesmentioning

confidence: 99%

Jak2 inhibitors: Rationale and role as therapeutic agents in hematologic malignancies

Sayyah¹,

Sayeski

2009

Curr Oncol Rep

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Although the Jak2-V617F mutation has generated strong awareness because of its causative role in myeloproliferative disorders, reports of Jak2 gene aberrations linked to hematologic malignancies have preceded those of V617F by nearly a decade. These malignant mutations include Jak2 amino acid substitutions, deletions, insertions, and chromosomal translocations. As a consequence, researchers are increasingly focused on identifying Jak2 inhibitors that suppress aberrant Jak2 kinase activity. Some of these inhibitors may one day become therapeutically beneficial for individuals with Jak2-related hematologic malignancies. This review summarizes various Jak2 mutations associated with hematologic malignancies and assesses some of the Jak2 inhibitors in the preclinical phase or in clinical trials. By reviewing these specific areas, we hope to have a better understanding of Jak2's role in hematologic malignancies and to shed light on the utility of Jak2 inhibitors.

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Leukaemia cutis in atypical chronic myeloid leukaemia with a t(9;22) (p24;q11.2) leading to BCR‐JAK2 fusion

Cited by 24 publications

References 1 publication

Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

Transforming and Tumorigenic Activity of JAK2 by Fusion to BCR: Molecular Mechanisms of Action of a Novel BCR-JAK2 Tyrosine-Kinase

Myeloproliferative disorders and its associated mutations

Jak2 inhibitors: Rationale and role as therapeutic agents in hematologic malignancies

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