Acute promyelocitic leukemia (APL) is characterized by the pathognomonic presence in leukemic blasts of the hybrid protein PML/RARA, that acts as a transcriptional repressor impairing the expression of genes that are critical to myeloid differentiation. Here, we show that primary blasts from APL patients express lower levels of the oncosuppressor protein PTEN, as compared to blast cells from other AML subtypes or normal bone marrow, and demonstrate that PML-RARA directly inhibits PTEN expression. We show that All-Trans Retinoic Acid (ATRA) triggers in APL cells an active chromatin status at the core regulatory region of the PTEN promoter, that allows the binding of the myeloid-regulating transcription factor PU.1, and, in turn, the transcriptional induction of PTEN. ATRA, via PML/RARA degradation, also promotes PTEN nuclear re-localization and decreases expression of the PTEN target Aurora A kinase. In conclusion, our findings support the notion that PTEN is one of the primary targets of PML/RARA in APL
Overexpression, polymorphisms, and mutations of the WT1 gene have been reported in several human tumors including acute myeloid leukemia (AML) and variably correlated with prognosis. Acute promyelocytic leukemia (APL) represents the AML subset disclosing higher WT1 expression levels; however, no WT1 studies specifically focused on APL have been conducted. We screened for the presence of mutations, SNP rs16754, and expression levels of WT1 gene in 103 adult patients with newly diagnosed APL. Fms-like tyrosine kinase (FLT3) mutations were analyzed as well. WT1 mutations were identified in four (4 %) patients. At least one copy of the minor SNP rs16754 allele (WT1(AG) or WT1(GG)) was detected in 30 (29 %) patients. Six patients (6 %) were homozygous for the minor allele (WT1(GG)) and this genotype was associated with higher WT1 mRNA copies (p = 0.018). FLT3 mutations were found in 37 % of patients and correlated with high WT1 mRNA expression (p = 0.004). Patients heterozygous or homozygous for the minor allele and patients homozygous for major (WT1(AA)) allele did not differ in terms of presenting features. In adult APL, WT1 gene mutational and polymorphic profile shows similarities with pediatric AML rather than with adult AML.
Summary Essential for cell survival, the 90 kD Heat Shock Proteins (HSP90) are molecular chaperons required for conformational stabilization and trafficking of numerous client proteins. Functional HSP90 is required for the stability of AKT, a serine‐threonine kinase phosphorylated in response to growth factor stimulation. AKT plays a crucial regulatory role in differentiation, cell cycle, transcription, translation, metabolism and apoptosis. Acute promyelocytic leukaemia (APL) is characterized by the presence of the promyelocytic leukaemia/retinoic acid receptor alpha (PML/RARA) fusion protein, which deregulates expression of several genes involved in differentiation and apoptosis. Here, we report inhibition of HSP90AA1 and HSP90AB1 isomer transcription in blasts isolated from patients with APL, associated with reduction of HSP90 protein expression and loss of control on AKT protein phosphorylation. We show that in vitro treatment of PML/RARA expressing cells with all‐trans retinoic acid (ATRA) up‐regulates HSP90 expression and stabilizes AKT. Addition of the HSP90‐inhibitor 17‐(allylamino)‐17‐demethoxygeldanamycin in combination with ATRA, blocks upregulation of AKT protein, indicating that HSP90 is necessary for ATRA action on AKT. This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
negative axillary nodes, successful treatment and a better prognosis. Intriguingly, breast cancer in young women is associated with adverse pathological factors, hormone receptor negativity, and HER2 (human epidermal growth factor receptor overexpression which explains worse outcome. 1 The screening and diagnosis of breast cancer patients at earlier stages benefits the patient, and also minimizes the financial burden. 5 The traditional clinical approach to treat both the in situ and invasive breast cancer involves the use of surgical, chemical and radiation based therapies. 6 The decision as to whether to have further chemotherapy that includes drugs such as Cyclophosphamide, 5-fluorouracil, carboplatin, taxane and anthracycline can cause considerable distress and common side effects such as anemia, nausea, vomiting, fertility issues, memory loss, menopause and menopausal problems, neuropathy, fatigue and hair loss-can be a difficult one. 7 In general, chemotherapy damages cells that are dividing, so the parts of the body such as mouth, intestines, skin, hair, and bone marrow where normal cells divide frequently are likely to be affected by chemotherapy. Most therapies which are administered to treat breast cancer are quiet toxic so it is better to select and use suitable therapy for the appropriate women. Some side effects of chemotherapy are less common but more serious medical conditions that need to be treated. 7 These include osteoporosis, heart problems and eye/vision problems. The limitations of chemotherapy, especially the narrow therapeutic index and the lack of discrimination for cancerous and non-cancerous cells have prompted the search for a greater target-directed approach to cancer treatment. Long-term side effects of chemotherapy could include damage to the heart, kidneys, lungs, nerves or reproductive organs. There is also a chance of developing a second cancer as a result of chemotherapy. 8
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