PCM1-JAK2 in Therapy Related Neoplasms
PCM1-JAK2 in Therapy Related Neoplasms
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.
Inclusion Criteria:

 -  • Myelodysplastic syndromes: the diagnosis of MDS must be confirmed by a bone marrow
 aspirate and/or biopsy : blast count must be < 20%; patients with any International
 Prognostic Score (IPSS) are eligible; patients with low or intermediate (INT)-1 IPSS
 must have a platelet count < 50x10⁹/L and/or absolute neutrophil count (ANC) <
 50x10⁹/L.

 -  Acute myeloid leukemia with multilineage dysplasia: the diagnosis of AML-TLD must
 be confirmed by a bone marrow aspirate and/or biopsy NOTE: there must be evidence
 of >= 20% blasts on the review of the bone marrow aspirate and/or biopsy; AML-TLD
 will be interpreted to include patients formerly diagnosed by
 French-American-British (FAB) criteria as refractory anemia with excess blasts in
 transformation (RAEB-t), as well as patients with no history of antecedent
 hematologic disorder who have AML which meets criteria for AML-TLD by World
 Health Organization (WHO) criteria; patients with AML-TLD must have a white blood
 cell (WBC) =< 30x10⁹/L documented within 4 weeks prior to study entry (two sets
 of counts that are 2 weeks apart will be taken); patients whose WBC has doubled
 within this period of time and is greater than 20x10⁹/L at the time of screening
 will not be eligible

 -  Patients have started therapy (cytotoxic agents and ionizing radiotherapy) at
 least 2 years ago.

 Exclusion Criteria:

 -  other therapy related neoplasms other than myelodplastic syndrome or acute myeloid
 leukemia