Deregulation of apoptosis-related genes is associated with PRV1 overexpression and JAK2 V617F allele burden in Essential Thrombocythemia and Myelofibrosis

<p>Abstract</p> <p>Background</p> <p>Essential Thrombocythemia (ET) and Primary Myelofibrosis (PMF) are Chronic Myeloproliferative Neoplasms (MPN) characterized by clonal myeloproliferation/myeloaccumulation without cell maturation impairment. The JAK2 V617F mutation and <it>PRV1 </it>gene overexpression may contribute to MPN physiopathology. We hypothesized that deregulation of the apoptotic machinery may also play a role in the pathogenesis of ET and PMF. In this study we evaluated the apoptosis-related gene and protein expression of BCL2 family members in bone marrow CD34⁺hematopoietic stem cells (HSC) and peripheral blood leukocytes from ET and PMF patients. We also tested whether the gene expression results were correlated with JAK2 V617F allele burden percentage, <it>PRV1 </it>overexpression, and clinical and laboratory parameters.</p> <p>Results</p> <p>By real time PCR assay, we observed that <it>A1, MCL1, BIK and BID</it>, as well as <it>A1, BCLW </it>and <it>BAK </it>gene expression were increased in ET and PMF CD34⁺cells respectively, while pro-apoptotic <it>BAX </it>and anti-apoptotic <it>BCL2 </it>mRNA levels were found to be lower in ET and PMF CD34⁺cells respectively, in relation to controls. In patients' leukocytes, we detected an upregulation of anti-apoptotic genes <it>A1, BCL2, BCL-X_L</it>and <it>BCLW</it>. In contrast, pro-apoptotic <it>BID </it>and <it>BIM_EL</it>expression were downregulated in ET leukocytes. Increased BCL-X_Lprotein expression in PMF leukocytes and decreased BID protein expression in ET leukocytes were observed by Western Blot. In ET leukocytes, we found a correlation between JAK2 V617F allele burden and <it>BAX, BIK and BAD </it>gene expression and between <it>A1, BAX </it>and <it>BIK </it>and <it>PRV1 </it>gene expression. A negative correlation between <it>PRV1 </it>gene expression and platelet count was observed, as well as a positive correlation between <it>PRV1 </it>gene expression and splenomegaly.</p> <p>Conclusions</p> <p>Our results suggest the participation of intrinsic apoptosis pathway in the MPN physiopathology. In addition, <it>PRV1 </it>and JAK2 V617F allele burden were linked to deregulation of the apoptotic machinery.</p

Relationship between SLCO1B(3) and ABCA(3) polymorphisms and imatinib response in chronic myeloid leukemia patients

Background: Genetic variations in membrane transporters may contribute to imatinib mesylate (IM) resistance in chronic myeloid leukemia (CML).Objective: To investigate the relationship between SLCO1B3, SLCO1A2, and ABCA3 polymorphisms and IM response in CML patients.Methods: Patients in chronic phase CML (N = 118) were studied. All patients were treated with a standard dose of IM (400 mg/day) and classified into one of the two groups according to their responses. Major molecular response (MMR) and complete molecular response (CMR) were evaluated. Criteria for response failure were established according to European LeukemiaNet (2009). Analysis of the SLCO1B3 c.334T > G (rs4149117) and c.699G > A (rs7311358), SLCO1A2 c.516A > C (rs11568563) and c.-62361G > A (rs3764043), and ABCA3 c.1755C > G (rs323043) and c.4548-191C > A (rs150929) polymorphisms was carried out by real-time polymerase chain reaction.Results: SLCO1A2 and ABCA3 polymorphisms have similar frequencies between responders and nonresponders. SLCO1B3 699GG and 344TT genotypes were more frequent in the responder group (63.8%) than in the non-responder group (44.7%, P = 0.042). Furthermore, carriers of 699GA/AA and 334TG/GG genotypes presented a higher probability of not responding to the standard dose of IM (odds ratio: 2.17; 95% confidence interval: 1.02-4.64, P = 0.04). Poor CMR for ABCA3 4548-91C > A was observed in patients with the CC/CA genotype when compared to AA carriers in the responder group (P = 0.014).Conclusions: SLCO1B3 699GG and 344TT genotypes are associated with non-response to IM, while ABCA3 4548-91 CC/CA genotypes are related to poor CMR in CML patients treated with standard-dose imatinib.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Univ São Paulo, Fac Ciencias Farmaceut, Dept Anal Clin & Toxicol, BR-05508000 São Paulo, SP, BrazilSanta Casa Misericordia São Paulo, Dept Hematol & Hemoterapia, São Paulo, BrazilHosp Brigadeiro, Dept Hematol, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Oncol Clin & Expt, São Paulo, BrazilUniversidade Federal de São Paulo, Dept Oncol Clin & Expt, São Paulo, BrazilFAPESP: 09/54184-0Web of Scienc

Acute myeloid leukemia: update in diagnosis and treatment in Brazil

International audienc

Acute myeloid leukemia: update in diagnosis and treatment in Brazil

Objective: To identify how the Brazilian hematology centerstreated and diagnosed cases of acute myeloid leukemia in 2009.Methods: An epidemiological observational multicenter study of11 listed Brazilian centers that treat acute myeloid leukemia andperform bone marrow transplantation. Data were collected fromclinical charts of patients with acute myeloid leukemia treatedat the said centers between 2005 and 2009. The availability forimmunophenotyping and cytogenetic tests was assessed. Results:During 2009, a total of 345 new cases of acute myeloid leukemiawere diagnosed. Differences were noted in the tests performedbetween patients who initiated treatment at the center and thosereferred for treatment. Of the participating centers, 72% conductedsome type of molecular study in acute myeloid leukemia upondiagnosis. Conclusion: Treatment for acute myeloid leukemia inBrazil shows significantly inferior results when compared to othercenters worldwide