Hyperthermia Selectively Destabilizes Oncogenic Fusion Proteins.

The PML/RARα fusion protein is the oncogenic driver in acute promyelocytic leukemia (APL). Although most APL cases are cured by PML/RARα-targeting therapy, relapse and resistance can occur due to drug-resistant mutations. Here we report that thermal stress destabilizes the PML/RARα protein, including clinically identified drug-resistant mutants. AML1/ETO and TEL/AML1 oncofusions show similar heat shock susceptibility. Mechanistically, mild hyperthermia stimulates aggregation of PML/RARα in complex with nuclear receptor corepressors leading to ubiquitin-mediated degradation via the SIAH2 E3 ligase. Hyperthermia and arsenic therapy destabilize PML/RARα via distinct mechanisms and are synergistic in primary patient samples and in vivo, including three refractory APL cases. Collectively, our results suggest that by taking advantage of a biophysical vulnerability of PML/RARα, thermal therapy may improve prognosis in drug-resistant or otherwise refractory APL. These findings serve as a paradigm for therapeutic targeting of fusion oncoprotein-associated cancers by hyperthermia. SIGNIFICANCE: Hyperthermia destabilizes oncofusion proteins including PML/RARα and acts synergistically with standard arsenic therapy in relapsed and refractory APL. The results open up the possibility that heat shock sensitivity may be an easily targetable vulnerability of oncofusion-driven cancers.See related commentary by Wu et al., p. 300.

Non-gastric marginal zone B cell lymphoma: clinicopathologic features and treatment results.

The optimal treatment strategy and outcome of non-gastric marginal zone lymphoma (MZL) remains undefined. The role of rituximab and fludarabine in MZL has not been critically appraised and compared with conventional chemotherapy. We retrospectively analyzed 81 consecutive patients with non-gastric MZL (mucosa-associated lymphoid tissue lymphoma, n=66; splenic MZL, n=11; nodal MZL, n=4). As a group, the treatment results were favorable, with an overall response rate of 87% and a complete response (CR) rate of 73%. The CR rate was similar for conventional chemotherapy, and rituximab- and fludarabine-containing regimens. However, the relapse rate was significantly decreased in rituximab- and fludarabine-containing regimens. The use of rituximab and fludarabine was associated with acceptable side effects. For splenic MZL, splenectomy was significantly associated with a superior CR rate. Early stage, good performance status, and low international prognostic index risk scores significantly impacted on CR rate and survivals. Rituximab and fludarabine were safe for non-gastric MZL and resulted in more durable remissions.

MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer's disease by vitamin D and curcuminoids.

Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-ß 1-42 (Aß) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of ß-1,4-mannosyl-glycoprotein 4-ß-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aß phagocytosis. The transcription of MGAT3 stimulated by Aß distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aß in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aß. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study.