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

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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