AKT is a therapeutic target in myeloproliferative neoplasms.

The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F- or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with ruxolitinib in suppressing the growth of JAK2V617F-mutant SET2 cells. Importantly, MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.

Bone marrow pathology in relapsing polychondritis: high frequency of myelodysplastic syndromes.

Haemopathologic changes were studied in 19 patients (13 male, six female, age 33-85 years, mean 56 years) with relapsing polychondritis (RP). Anaemia was found in eight, thrombocytopenia in two and splenomegaly in three patients. A total of 17 bone marrow biopsies were obtained from seven individuals. Bone marrow evaluation revealed myelodysplastic syndromes (MDS) with marked trilineage hyperplasia and dysplasia in three cases. Since an excess of myeloblasts or an increase of CD34 positive progenitor cells was not seen, the disorders were designated as 'refractory anaemia' or with regard to the dysplastic megakaryopoiesis 'MDS, unclassifiable'. Two of the three patients died after 10 and 55 months of follow-up due to infectious complications. In a further patient, bone marrow analysis repeatedly showed an unexplained granulopoietic hyperplasia, which, however, was not dysplastic enough to allow a diagnosis of MDS. The remaining patients had clearly reactive changes. Our findings support the notion that RP is a heterogenous disorder and suggest that RP may at times represent a paraneoplastic phenomenon of an underlying MDS. Since HLA typing revealed a significantly increased frequency of the antigen DR4 (10/17 patients positive = 59%), we hypothesize that immunological imbalances due to the MDS in conjunction with a specific immunogenetic background may play key roles in the pathogenesis of RP in these patients.