PMID- 17976519
OWN - NLM
STAT- MEDLINE
DCOM- 20080107
LR  - 20121115
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 35
IP  - 11
DP  - 2007 Nov
TI  - Numerical gain and structural rearrangements of JAK2, identified by FISH, 
      characterize both JAK2617V>F-positive and -negative patients with Ph-negative 
      MPD, myelodysplasia, and B-lymphoid neoplasms.
PG  - 1668-76
AB  - OBJECTIVE: Current evidence suggests that the JAK2617V>F point mutation is 
      implicated in the pathogenesis of >90% of polycythemia vera (PV) patients, and in 
      approximately 50% of primary myelofibrosis (PMF) and essential thrombocythemia 
      patients. Novel JAK2 mutations were recently described in 5% to 15% of patients 
      that are JAK2617V>F-negative. Additionally, JAK2 is reported to form fusion 
      hybrids with three different genes. We, therefore, hypothesized that patients 
      with 9p24 chromosomal rearrangements or patients with Philadelphia chromosome 
      (Ph)-negative myeloproliferative disorders (MPDs), with or without +9/+9p 
      chromosomal abnormalities, might demonstrate additional and/or cryptic JAK2 
      structural rearrangements. METHODS: Metaphase and interphase cells were 
      retrospectively investigated from 39 patients using two JAK2 BAC fluorescence in 
      situ hybridization (FISH) probes on archived fixed cell suspensions. Of the 39 
      patients, 8 had PV with chromosome 9 abnormalities, 7 had PMF/MPD showing an 
      abnormal karyotype, 10 PV patients were cytogenetically normal, and 14 patients 
      had 9p24 chromosomal abnormalities. RESULTS: FISH studies revealed 11 
      JAK2617V>F-positive patients with JAK2 numerical and structural abnormalities. 
      Trisomy through hexasomy as well as JAK2 amplification (15-20 copies) was 
      observed in nine patients (PV, 6; non-Hodgkin lymphoma [NHL], 1; multiple 
      myeloma, 1; and MDS, 1), while JAK2 structural abnormalities were seen in two 
      patients (MDS and NHL). Among the seven patients negative for JAK2617V>F 
      mutation, two patients with MDS were observed with JAK2 rearrangements involving 
      NF-E2 and AML1. The status of JAK2617V>F mutation could not be determined in 13 
      patients, but FISH studies revealed both gain and rearrangements in three 
      patients. They include one patient with PV and +9p with three copies of JAK2 and 
      two patients with MDS and JAK2 relocations: one with NF-E2, while the other 
      patient with a TEL/ETV6 rearrangements also had tetrasomy for JAK2. CONCLUSION: 
      JAK2 FISH studies revealed two types of JAK2 rearrangements among patients with 
      Ph-negative MPDs and non-MPDs: gain and/or structural rearrangements. Gain and 
      amplification of JAK2 was primarily observed in patients that were 
      JAK2617V>F-positive (9 of 11), irrespective of the diagnosis, while 
      rearrangements of JAK2 were frequently seen in patients who lacked the JAK2617V>F 
      mutation with either MDS or AML (5 of 6). Three different JAK2 abnormalities were 
      identified in one clone for the first time in two patients with PV. The data also 
      identified a myriad of JAK2 rearrangements, including a novel JAK2-NF-E2 
      interaction, JAK2 translocation to chromosomes 3, 4, 12, 14, and 21 and detection 
      of the previously described rare TEL/ETV6-JAK2 translocation. These observations 
      suggest that JAK2 attracts multiple gene partners and may contribute to disease 
      progression in patients with MDS and B-cell malignancies, while the JAK2 copy 
      number appears to be important in pathogenesis of Ph-negative MPDs.
FAU - Najfeld, Vesna
AU  - Najfeld V
AD  - Department of Pathology, Tumor Cytogenetics Laboratory, The Mount Sinai School of 
      Medicine, New York, NY 10029, USA. vesna.najfeld@mssm.edu
FAU - Cozza, Amanda
AU  - Cozza A
FAU - Berkofsy-Fessler, Windy
AU  - Berkofsy-Fessler W
FAU - Prchal, Josef
AU  - Prchal J
FAU - Scalise, Angela
AU  - Scalise A
LA  - eng
GR  - 1P01CA108671-01A2/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - EC 2.7.10.2 (Janus Kinase 2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Case-Control Studies
MH  - Female
MH  - Gene Dosage
MH  - Gene Rearrangement
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Janus Kinase 2/*genetics/metabolism
MH  - Leukemia, B-Cell/*genetics
MH  - Lymphoma, B-Cell/*genetics
MH  - Male
MH  - Middle Aged
MH  - Mutation
MH  - Myeloproliferative Disorders/*genetics
MH  - Philadelphia Chromosome
MH  - Protein Transport
MH  - Retrospective Studies
EDAT- 2007/11/03 09:00
MHDA- 2008/01/08 09:00
CRDT- 2007/11/03 09:00
PHST- 2007/05/16 00:00 [received]
PHST- 2007/08/20 00:00 [revised]
PHST- 2007/08/20 00:00 [accepted]
PHST- 2007/11/03 09:00 [pubmed]
PHST- 2008/01/08 09:00 [medline]
PHST- 2007/11/03 09:00 [entrez]
AID - S0301-472X(07)00534-6 [pii]
AID - 10.1016/j.exphem.2007.08.025 [doi]
PST - ppublish
SO  - Exp Hematol. 2007 Nov;35(11):1668-76. doi: 10.1016/j.exphem.2007.08.025.