Detection of PCM1-JAK2 Fusion Gene by FISH in the Two Types of t-MDS/AML and Relationship Between PCM1-JAK2 Fusion Gene and Cumulative Dose, Dose Intensity Clinical Trial
Official title:
PCM1-JAK2 Fusion Gene Detection in Patients With Therapy Related Myelodysplastic Syndrome / Acute Myeloid Leukemia Patients
The term "therapy-related" leukemia is descriptive and is based on a patient's history of
exposure to cytotoxic agents. Although a causal relationship is implied, the mechanism
remains to be proven. These neoplasms are thought to be the direct consequence of mutational
events induced by the prior therapy Therapy-related myelodysplastic syndromes / acute myeloid
leukemia (t- MDS / t-AML) is now considered a single entity, called therapy-related myeloid
neoplasms based on the current World Health Organization WHO classification2,. It is a
well-recognized clinical syndrome occurring as a late complication following Cytotoxic agents
and ionizing radiotherapy in the treatment of most cancer types: Hodgkin lymphoma (HL),
non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), sarcoma, and ovarian and
testicular cancerThe incidence of t-MDS/AML following conventional therapy ranges from 0.8%
to 6.3% at 20 years. The median time to development of t-MDS/AML is 3 to 5 years, with the
risk decreasing markedly after the first decade Two types of t-MDS/AML are recognized in the
WHO classification depending on the causative therapeutic exposure: an alkylating
agent/radiation-related type and a topoisomerase II inhibitor-related type. Alkylating
agent-related t-MDS/AML usually appears 4 to 7 years after exposure to the mutagenic agent
.The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the
long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2
(JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and
reunion at bands 8p11 and 9q3410Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1
mediate an oligomerization that brings together the linked JAK2 domains resulting in a
constitutively activated tyrosine kinase domain of JAK2The most common mechanism for JAK2
activation in hematologic malignancies is the point mutation at position 617 (V617F).
The consequences of JAK2 activation are neoplastic transformation and abnormal cell
proliferation in various malignancies
- So, translocations involving the JAK2 locus are considered of oncogenic importance in
acute leukemias and myelodysplastic/ myeloproliferative diseases.
- Patients with this abnormality present with broad clinical spectrum ranging from chronic
to acute hematological diseases with myeloid or lymphoid appearance
The term "therapy-related" leukemia is descriptive and is based on a patient's history of
exposure to cytotoxic agents. Although a causal relationship is implied, the mechanism
remains to be proven. These neoplasms are thought to be the direct consequence of mutational
events induced by the prior therapy .
Therapy-related myelodysplastic syndromes / acute myeloid leukemia (t- MDS / t-AML) is now
considered a single entity, called therapy-related myeloid neoplasms based on the current
World Health Organization WHO classification2,. It is a well-recognized clinical syndrome
occurring as a late complication following Cytotoxic agents and ionizing radiotherapy in the
treatment of most cancer types: Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL), acute
lymphoblastic leukemia (ALL), sarcoma, and ovarian and testicular cancer3,4.
The characteristics of therapy-related myeloid neoplasm and the timing of its development
after a primary diagnosis depend on the exposure to specific agents as well as the cumulative
dose and dose intensity of the preceding cytotoxic therapy 5.
The incidence of t-MDS/AML following conventional therapy ranges from 0.8% to 6.3% at 20
years. The median time to development of t-MDS/AML is 3 to 5 years, with the risk decreasing
markedly after the first decade 6.
Two types of t-MDS/AML are recognized in the WHO classification depending on the causative
therapeutic exposure: an alkylating agent/radiation-related type and a topoisomerase II
inhibitor-related type. Alkylating agent-related t-MDS/AML usually appears 4 to 7 years after
exposure to the mutagenic agent .
Approximately two-thirds of patients present with MDS and the remainder with AML with
myelodysplastic features. Patients frequently present with cytopenias. Multilineage dysplasia
is often present 7.
In this classic form of therapy-related leukemia that follows treatment with alkylating
agents and/or radiation therapy, the blood and bone marrow findings resemble those seen in
primary MDS, although the degree of dysgranulopoiesis and dysmegakaryocytopoiesis is
typically greater 8.
In contrast to alkylating agent t-MDS/AML, AML secondary to topoisomerase II inhibitors often
does not have a preceding myelodysplastic phase, and presents as overt acute leukemia, often
with a prominent monocytic component. The latency period between the initiation of treatment
with topoisomerase II inhibitors and the onset of leukemia is brief, with a median of 2 to 3
years 9.
The reciprocal translocation t(8;9) (p22;p24) between the short arm of chromosome 8 and the
long arm of chromosome 9 is a recurrent abnormality that fuses the Janus activated kinase 2
(JAK2) to the human autoantigen pericentriolar material 1 gene (PCM1) , with breakage and
reunion at bands 8p11 and 9q341010.
PCM1 encodes a large protein of 228kDa containing several potential coiled-coil domains in
its aminoterminal part. This protein is localized in cytoplasmatic granules referred to as
centriolar satellites. It is supposed to play a crucial role in the assembly of centrosomal
proteins, microtubule organisation, and in the progression of cell cycle11.
Due to PCM1-JAK2 gene fusion, the coiled-coil domains of PCM1 mediate an oligomerization that
brings together the linked JAK2 domains resulting in a constitutively activated tyrosine
kinase domain of JAK212, 13.
JAK2 is a member of the Janus family of tyrosine kinases (JAK1, JAK2, JAK3, TYK2). These
non-receptor tyrosine kinases play a significant role in various signal transduction pathways
that regulate cellular survival, proliferation, differentiation, and apoptosis. The protein
is formed of seven domains. The JH2 domain (pseudokinase domain, kinase-like domain) is
located in exon 14 and has an essential negative autoregulatory function14.
The most common mechanism for JAK2 activation in hematologic malignancies is the point
mutation at position 617 (V617F).
The consequences of JAK2 activation are neoplastic transformation and abnormal cell
proliferation in various malignancies15.
- So, translocations involving the JAK2 locus are considered of oncogenic importance in
acute leukemias and myelodysplastic/ myeloproliferative diseases.
- Patients with this abnormality present with broad clinical spectrum ranging from chronic
to acute hematological diseases with myeloid or lymphoid appearance 16.
Fluorescence in situ hybridization (FISH) is a kind of cytogenetic technique that allows the
visualization of defined nucleic acid sequences in particular cellular or chromosomal sites
by hybridization of complementary fluorescently labeled probe sequences within intact
metaphase or interphase cells.
The fluorescent probes are nucleic acid labeled with fluorescent groups and can bind to
specific DNA/RNA sequences. Fluorescence microscopy can be used to find out where the
fluorescent probe is bound to the chromosomes17.
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