Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Germline variants within the transcription factor RUNX1 are associated with familial platelet disorder and acute leukemia in over 40% of carriers. At present, the somatic events triggering leukemic transformation appear heterogeneous and profiles of leukemia initiation across family members are poorly defined. We report a new RUNX1 family where three sisters harboring a germline nonsense RUNX1 variant, c.601C>T (p.(Arg201*)), developed acute myelomonocytic leukemia (AML) at 5 years of age. Whole-exome sequencing of tumor samples revealed all three siblings independently acquired variants within the JAK-STAT pathway, specifically targeting JAK2 and SH2B3 (a negative regulator of JAK2), while also sharing the 46/1 haplotype linked with sporadic JAK2-positive myeloproliferative neoplasms. In-depth chromosomal characterization of tumors revealed acquired copy number gains and uniparental disomy amplifying RUNX1, JAK2 and SH2B3 variants, highlighting the significance of co-operation between these disrupted pathways. One sibling, presenting with myelodysplasia at 14 years, had no evidence of clonal or subclonal JAK2 or SH2B3 variants, suggesting the latter were specifically associated with leukemic transformation in her sisters. Collectively, the clinical and molecular homogeneity across these three young siblings provides the first notable example of convergent AML evolution in a RUNX1 pedigree, with the recurrent acquisition of JAK-STAT pathway variants giving rise to high-risk AML, characterized by chemotherapy resistance and relapse.
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PMID:Recurrent somatic JAK-STAT pathway variants within a RUNX1-mutated pedigree. 2851 14

Platelets have an important role in hemostasis. Platelet disorders occur when too few or too many platelets are present, or when platelet functions are abnormal. Thrombocytopenia, defined as a platelet count less than 150,000/mcL, can be acute or chronic and congenital or acquired. Severe thrombocytopenia is associated with life-threatening bleeding and thrombotic complications. A comprehensive history and physical examination are central to the diagnostic approach. These elements should focus on identification of concurrent conditions associated with thrombocytopenia and differentiation among three mechanisms: decreased platelet production, increased platelet consumption, and platelet sequestration. Although previously thought to be the result of a single process, thrombocytopenia often is due to a combination of factors. Thrombocytosis is present when the platelet count is elevated. The principal types are essential (primary) thrombocythemia and reactive (secondary) thrombocytosis. Essential thrombocythemia is a myeloproliferative neoplasm associated with mutations of genes that regulate thrombopoiesis (eg, JAK2). It can lead to thrombotic and hemorrhagic complications. Reactive thrombocytosis frequently is encountered in the family medicine setting. It rarely causes vascular complications or requires management beyond that required for the underlying condition. Written permission from the American Academy of Family Physicians is required for reproduction of this material in whole or in part in any form or medium.
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PMID:Hematologic Conditions: Platelet Disorders. 3161 66