SPECTRUM OF AFFECTED GENES IN UKRAINIAN PATIENTS WITH PRIMARY MYELOFIBROSIS

In this study we aimed to identify the spectrum of affected genes in Ukrainian patients diagnosed with primary myelofibrosis (PMF). DNA samples were obtained from peripheral blood leukocytes of 30 Ukrainian PMF patients. Using Whole Exome Sequencing, we detected previously reported and unreported sequence variants considered as pathogenic or potentially pathogenic. Canonical mutations of usual MPN-driver genes were detected in 70% of PMF patients, including JAK2V617F in 43.3%, MPLW515 in 10% and CALRmutations (type 1-like and 2-like) in 16.7% of patients. Also, a non-canonical MPLP222S variant was detected in one patient negative for these mutations. However, in cell culture assay, MPLP222S expression in Ba/F3 cells did not demonstrate differences in phosphorylation of JAK/STAT signaling proteins in response to TPO stimulation compared to MPLWT expression. Overall, more pathogenic and potentially pathogenic sequence variants were found among PMF patients negative for canonical mutations in three driver genes (JAK2, MPL andCALR), compared to patients, positive for one of these mutations. The mean numbers of variants were 5 (range: 4 7) versus 3.3 (range: 1 9), respectively (p = 0.03). The most frequently affected among Ukrainian PMF patients were genes ASXL1, PEG3, EZH2, ATM, U2AF1, andCDH23in addition to JAK2, MPL andCALR. Pathogenic or potentially pathogenic sequence variants of ASXL1and EZH2genes were identified in 23.3% and 16.7% of cases, respectively. Genes JARID2, RBBP8, RTEL1, SUZ12, BRCA2, LAMB4, NF1, RBM12B, RBM43, and RBP3 were recurrently affected in PMF patients who were also positive for usual mutations in three driver genes. Among PMF patients negative for usual mutations in three driver genes recurrently affected genes were DNMT3Aand TET2in addition to mentioned earlier, and some genetic variants were identified in RTEL1, SUZ12, CBL, CUX1, FLT3LGand UMODL1genes in single cases. Also, we identified several genes affected in single cases (KIT, SF3B1, GNAS) in PMF patients negative for canonical mutations in three driver genes which may be potential MPN drivers

The Myth of Equality in the Employment Relation

Although it is widely understood that employers and employees are not equally situated, we fail adequately to account for this inequality in the law governing their relationship. We can best understand this inequality in terms of status, which encompasses one’s level of income, leisure and discretion. For a variety of misguided reasons, contract law has been historically highly resistant to the introduction of status-based principles. Courts have preferred to characterize the unfavorable circumstances that many employees face as the product of unequal bargaining power. But bargaining power disparity does not capture the moral problem raised by inequality in the employment relation, and thus, it has failed to inspire any meaningful attempt to address that inequality. By contrast, a status-based approach would motivate several common sense doctrinal changes. The persistent myth of equality is still more paradoxical in the context of labor law. Due to political constraints and several sources of uncertainty about its future, the National Labor Relations Act was limited to a bare bones framework for collective bargaining. Later amendments and judicial interpretations entrenched a strictly procedural interpretation of the Act oriented toward the goal of minimizing commercial disruption rather than disrupting status inequality. The present regime sustains a false image of unions as equal in strength to employers, in need of only an illusive level playing field. As a result, it does not effectively mitigate the negative dimensions of social status stemming from employment. A few modest changes would help re-orient or at least broaden the Act so that unions can play a meaningful role in mitigating status inequality