The role of MYC and PP2A in the initiation and progression of myeloid leukemias

The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other's activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias

Disclosing HIV Serostatus to sexual partners among HIV infected women in KisiI DistricT, Kenya: A qualitative study

Study objective: As the rates of HIV infection continues to soar in many parts of the world, concerted efforts have been mounted on counseling to help HIV infected individuals disclose their serostatus to their sexual partners. However, various studies have continued to show few seropositive women disclosing their status to their sexual partners and this has become an important impediment to the efforts made in HIV prevention and treatment. The study aimed at establishing factors that influence women’s decision to disclose HIV serostatus to their sexual partners. Methods: The study was a qualitative study conducted in Kisii district hospital, western Kenya among 87 purposively selected HIV infected women enrolled at a Patient Support Center and 8 key informants. Focus group discussions and key informants interviews were used to collect the data. Aspects of disclosure that were assessed included; the prevalence of disclosure, the reasons that enhanced/ de-enhanced disclosure, the reaction of the sexual partner after being disclosed to and the intent to disclose among women who had not disclosed. Data was analysed by Text2based Beta Softwares Results: Out of the 87 participants 59 had disclosed their HIV serostatus to their sexual partners. Of those participants who had not disclosed (28) 19 had no intention of ever disclosing. Main factors that enhanced disclosure were a feeling that a partner needed to know or to gain the partner’s support while factors that exhibited disclosure were expressed as; fear of being abandoned by the sexual partner, being accused of infidelity or the possibility of the sexual partner withdrawing his economic support. Conclusion: The reasons given by the study participants are of public health importance as they may have limited most women to appropriate health care or ability to engage in safer sexual behaviours, which are both tantamount to HIV/AIDS control effort. Keywords: Disclosure, HIV serostatus, sexual partners, HIV infected women, Keny

Cytogenetic and molecular analysis of the acute monocytic leukemia cell line THP-1 with an MLL-AF9 translocation

Cell lines derived from patients with leukemia are used in many molecular biology studies. Here we report the cytogenetic analysis of the THP-1 cell line using G-banding, fluorescence in situ hybridization (FISH), and spectral karyotyping (SKY), and the molecular characterization of the MLL-AF9 rearrangement by RT-PCR. The THP-1 cell line was established from the peripheral blood of a 1-year-old boy with acute monocytic leukemia (AML-M5). THP-1 is near-diploid and consists of two related subclones with a number of aberrations, including the t(9;11), associated with AML M5. The use of FISH allowed us to identify and characterize otherwise hidden cytogenetic rearrangements, which include duplication of the 3' portion of MLL in the derivative 9 chromosome and a deletion of the 5' portion of the AF9 gene involved in the translocation. In addition to confirming the FISH results, SKY allowed for a more precise characterization of the karyotype of THP-1 and allowed us to identify other abnormalities in this cell line, including der(1)t(1;12), der(20)t(1;20), deletions 6p, 12p, and 17p, trisomy 8, and monosomy 10. Sequencing of the RT-PCR product showed a direct in-frame fusion product on the derivative chromosome 11 between exon 6 (exon 9) of MLL and exon 5 of AF9, which is most commonly involved in MLL-AF9 translocations. This study demonstrates that combining different techniques to achieve a more precise characterization of the THP-1 cell line provides important information that will be valuable for understanding the critical events required for leukemogenesis

Further characterization of complex chromosomal rearrangements in myeloid malignancies: spectral karyotyping adds precision in defining abnormalities associated with poor prognosis

The mixed lineage leukemia gene (MLL, also known as HRX, ALL-1 and Htrx) located at 11q23 is involved in translocations with over 40 different chromosomal bands in a variety of leukemia subtypes. Here we report our analysis of a rare but recurring translocation, t(11;15)(q23;q14). This translocation has been described in a small subset of cases with both acute myeloblastic leukemia and ALL. Recent studies have shown that MLL is fused to AF15q14 in the t(11;15). Here we analyse a sample from another patient with this translocation and confirm the presence of an MLL-AF15q14 fusion. However, we have also identified and cloned another fusion transcript from the same patient sample. In this fusion transcript, MLL is fused to a novel gene, MLL partner containing FYVE domain (MPFYVE). Both MLL-AF15q14 and MLL-MPFYVE are in-frame fusion transcripts with the potential to code for novel fusion proteins. MPFYVE is also located on chromosome 15, approximately 170 kb telomeric to AF15q14. MPFYVE contains a highly conserved motif, the FYVE domain which, in other proteins, has been shown to bind to phosphotidyl-inositol-3 phosphate (PtdIns(3)P). The MLL-MPFYVE fusion may be functionally important in the leukemia process in at least some patients containing this translocation

Regulation and role of the PP2A-B56 holoenzyme family in cancer

Protein phosphatase 2A (PP2A) inactivation is common in cancer, leading to sustained activation of pro-survival and growth-promoting pathways. PP2A consists of a scaffolding A-subunit, a catalytic C-subunit, and a regulatory B-subunit. The functional complexity of PP2A holoenzymes arises mainly through the vast repertoire of regulatory B-subunits, which determine both their substrate specificity and their subcellular localization. Therefore, a major challenge for developing more effective therapeutic strategies for cancer is to identify the specific PP2A complexes to be targeted. Of note, the development of small molecules specifically directed at PP2A-B56α has opened new therapeutic avenues in both solid and hematological tumors. Here, we focus on the B56/PR61 family of PP2A regulatory subunits, which have a central role in directing PP2A tumor suppressor activity. We provide an overview of the mechanisms controlling the formation and regulation of these complexes, the pathways they control, and the mechanisms underlying their deregulation in cancer

A t(11;15) fuses MLL to two different genes, AF15q14 and a novel gene MPFYVE on chromosome 15

The mixed lineage leukemia gene (MLL, also known as HRX, ALL-1 and Htrx) located at 11q23 is involved in translocations with over 40 different chromosomal bands in a variety of leukemia subtypes. Here we report our analysis of a rare but recurring translocation, t(11;15)(q23;q14). This translocation has been described in a small subset of cases with both acute myeloblastic leukemia and ALL. Recent studies have shown that MLL is fused to AF15q14 in the t(11;15). Here we analyse a sample from another patient with this translocation and confirm the presence of an MLL-AF15q14 fusion. However, we have also identified and cloned another fusion transcript from the same patient sample. In this fusion transcript, MLL is fused to a novel gene, MLL partner containing FYVE domain (MPFYVE). Both MLL-AF15q14 and MLL-MPFYVE are in-frame fusion transcripts with the potential to code for novel fusion proteins. MPFYVE is also located on chromosome 15, approximately 170 kb telomeric to AF15q14. MPFYVE contains a highly conserved motif, the FYVE domain which, in other proteins, has been shown to bind to phosphotidyl-inositol-3 phosphate (PtdIns(3)P). The MLL-MPFYVE fusion may be functionally important in the leukemia process in at least some patients containing this translocation