Review on t(3;9)(p13;q34.1) FOXP1/ABL1, with data on clinics, and the genes involved....

GSK3beta interaction protein (GSKIP) is a negative regulator of GSK3B (GSK3 beta) which is a highly conserved serine-threonine kinase involved in many cellular processes including glycogen metabolism, proliferation, differentiation, and development. GSKIP directly interacts with GSK3B through its C-terminal conserved GSK3B -binding domain (GID) and negatively regulates GSK3B in the Wnt/ beta -catenin signaling pathway. The overexpression of GSKIP may result in the activation of the Wnt pathway involved in hematopoietic stem cell homeostasis and normal megakaryopoiesis and in the development of leukemia stem cells in acute myeloid leukemia (AML). In a mouse model, GSK3B allelic deletion results in a myelodysplastic syndrome that, when combined with GSK3A deletion, leads to AML The germline duplication of ATG2B and GSKIP, both located in 14q32.2, predisposes to the development of familial myeloproliferative neoplasms with autosomal dominant inheritance, in particular essential thrombocythemia progressing to leukemia. Overexpression of ATG2B and GSKIP enhances megakaryocyte progenitor differentiation by increasing progenitor sensitivity to thrombopoietin. Both genes cooperate with somatic JAK2, MPL and CALR mutations and their overexpression provides a growth advantage to hematopoietic cells carrying these driver mutations that may explain the familial aggregation and the progression of essential thrombocythemia to myelofibrosis and leukemia....

Review on i(18)(q10) in haematological malignancies, with data on the genes involved....

Fanconi anemia (FA) is a rare human recessive syndrome featuring bone marrow failure, myelodysplasia, and predisposition to cancer as well as chromosome fragility and hypersensitivity to DNA interstrands crosslinking agents. FA was described in 1927 by the Swiss pediatrician Giuseppe Fanconi, which reported a first family with three affected sibling presenting developmental defects and anemia. FA cells are hypersensitive, at both cellular and chromosomal levels, to the exposure to DNA interstrands crosslinking agents, like mitomycin C, diepoxybutane, cis-platinum or photoactivated psoralen. The chromosomal response to DNA interstrands crosslinks (ICLs)-inducing agents is so typical that the observation of both the induced frequency of chromosome aberrations and their type, i.e. tri- and quadri-radials, is considered the best diagnostic criteria for FA. Indeed, looking simply at the clinical hallmarks of the patients, it is difficult to distinguish FA patients from several other bone marrow failure syndromes. Alternatively, since the FA cells need more time to pass through both G2 and S phases than normal cell, the analysis by flow cytometry of the over accumulation of the FA cells in G2 following exposure to ICL-inducing agents could be a useful approach for diagnosis. More recently, molecular and biochemical approaches looking at gene mutations, proteins expression and/or post-translational modifications are used to validate cytogenetics conclusions. To date 19 different genes (FANC) have been associated to FA. The FANC proteins constitute a pathway which essential function is to deal with replication stress assuring the transmission of a stable genome from one cell to the daughters and acting both during replication, to cope with stalled replication forks, but also in G2 and M phases, to resolve un-replicated or not fully replicated regions before telophase. For review: Duxin and Walter, 2015; Bogliolo and Surralles, 2015; Walden and Deans, 2014; Soulier 2011; Lobitz and Velleuer, 2006....