Clonal analyses define the relationships between chromosomal abnormalities and JAK2V617F in patients with Ph-negative myeloproliferative neoplasms.
OBJECTIVE
JAK2V617F occurs in approximately 93% of patients with polycythemia vera and approximately 50% of patients with either primary myelofibrosis or essential thrombocythemia. Chromosomal abnormalities are detected in 50% of patients with primary myelofibrosis, 29% with polycythemia vera, and 8% to 10% with essential thrombocythemia. The relationship between the presence of such chromosomal abnormalities and the JAK2V617 allele burden, and the role that each of these genetic events play in the origins and progression of the myeloproliferative neoplasms (MPNs), remain unclear.


METHODS
Individual hematopoietic colonies were assayed in vitro from the CD34(+) cells of six JAK2V617F-positive MPN patients with marker chromosomal abnormalities. Colonies were simultaneously analyzed for JAK2 genotype and chromosomal abnormalities.


RESULTS
Among the 248 colonies assayed from cultures containing 500 CD34(+) cells, chromosomal abnormalities were detected in 5% of colonies with wild-type JAK2, 32% of JAK2V617F heterozygous colonies and 56% of JAK2V617F homozygous colonies. Overall, 92% of chromosomally abnormal colonies were also JAK2V617F homozygous. Although 54 colonies contained wild-type JAK2 exclusively, 4 of these colonies were characterized by chromosomal abnormalities.


CONCLUSIONS
This study indicates that MPN hematopoietic progenitor cells do not necessarily always acquire genetic events in the same sequence. (Chromosomally abnormal progenitor cells are closely associated with JAK2V617F homozygosity; p=0.0001.). Chromosomal abnormalities such as +8, +9 can occasionally precede acquisition of JAK2V617F. These findings support the existence of earlier genetic events that precede JAK2V617F or cytogenetic abnormalities in MPN hematopoietic progenitor cells.
Wang
Xiaoli
X
Division of Hematology and Oncology, The Myeloproliferative Disorders Program, Tisch Cancer Institute, New York, NY, USA.
LeBlanc
Amanda
A
Gruenstein
Steven
S
Xu
Mingjiang
M
Mascarenhas
John
J
Panzera
Brenda
B
Wisch
Nathaniel
N
Parker
Charles
C
Goldberg
Judith D
JD
Prchal
Josef
J
Hoffman
Ronald
R
Najfeld
Vesna
V
D000368:Aged; D002869:Chromosome Aberrations; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D005260:Female; D005838:Genotype; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics*; D007621:Karyotyping; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D017354:Point Mutation; D011087:Polycythemia Vera / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D055728:Primary Myelofibrosis / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D053628:Receptors, Thrombopoietin / Q000235:genetics; D013920:Thrombocythemia, Essential / Q000201:enzymology / Q000235:genetics* / Q000473:pathology
D053628:Receptors, Thrombopoietin; C082218:MPL protein, human; C507924:JAK2 protein, human; D053614:Janus Kinase 2