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The hallmark of acute lymphoblastic leukemia (ALL) is a progressive appearance of malignant cell behavior that is triggered by the evolution of altered gene function. ALL has traditionally been viewed as a genetic disease; however, epigenetic defects also play an important role. DNA promoter methylation has gained increasing recognition as an important mechanism for transcriptional silencing of tumor-suppressor genes. Hypermethylation may contribute to the pathogenesis of leukemias providing an alternative route to gene mutation. We have reported that gene methylation in ALL cells is the most important way to inactivate cancer-related genes in this disease. In fact, this epigenetic event can help to inactivate tumor-suppressive apoptotic or growth-arresting responses and has prognostic impact in B- and T-ALL. The presence in individual tumors of multiple genes simultaneously methylated is an independent factor of poor prognosis in both childhood and adult ALL in terms of disease-free survival and overall survival. Moreover, methylation status is able to redefine the prognosis of selected ALL groups with well-established prognostic features. [ABSTRACT FROM AUTHOR]

Background and Objectives: Cancer testis antigens (CTA) provide attractive targets for cancer-specific immunotherapy. Although CTA genes are expressed in some normal tissues, such as the testis, this immunologically protected site lacks MHC I expression and as such, does not present self antigens to T cells. To date, CTA genes have been shown to be expressed in a range of solid tumors via demethylation of their promoter CpG islands, but rarely in chronic myeloid leukemia (CML) or other hematologic malignancies., Design and Methods: In this study, the methylation status of the HAGE CTA gene promoter was analyzed by quantitative methylation-specific polymerase chain reaction (MSP) and sequencing in four Philadelphia-positive cell lines (TCC-S, K562, KU812 and KYO-1) and in CML samples taken from patients in chronic phase (CP n=215) or blast crisis (BC n=47). HAGE expression was assessed by quantitative reverse transcriptase-polymerase chain reaction., Results: The TCC-S cell line showed demethylation of HAGE that was associated with over-expression of this gene. HAGE hypomethylation was significantly more frequent in BC (46%) than in CP (22%) (p=0.01) and was correlated with high expression levels of HAGE transcripts (p<0.0001). Of note, in CP-CML, extensive HAGE hypomethylation was associated with poorer prognosis in terms of cytogenetic response to interferon (p=0.01) or imatinib (p=0.01), molecular response to imatinib (p=0.003) and progression-free survival (p=0.05). INTERPRETATIONS AND CONCLUSION: The methylation status of the HAGE promoter directly correlates with its expression in both CML cell lines and patients and is associated with advanced disease and poor outcome.

Background and Objectives: Interferon-alpha (IFN-alpha) has proven useful for treating chronic myeloid leukemia (CML). However, only 7% of patients achieve a complete cytogenetic response. Although efforts to understand the molecular basis of this resistance to IFN-alpha have been made, the mechanism is still unknown. Because suppressor of cytokine signaling (SOCS) proteins are negative regulators of cytokine-induced signaling, it has been hypothesized that aberrant SOCS expression could confer resistance against cytokine therapy., Design and Methods: In order to analyze the role of SOCS-1 in the acquisition of IFN-alpha resistance in this setting, we examined SOCS-1 mRNA expression using reverse transcription polymerase chain reaction (RT-PCR) in 75 newly diagnosed chronic phase-CML patients who received IFN-alpha therapy., Results: SOCS-1 was constitutively expressed in 49 (65%) of 75 CML patients at diagnosis. Constitutive SOCS-1 expression was more frequently observed among Hasford high-risk patients (p = 0.05) and was also independently associated with a shorter median progression-free survival time (p = 0.001) and poor cytogenetic response to IFN-alpha treatment (p 0.0001)., Interpretation and Conclusions: Our data indicate that constitutive expression of SOCS-1 occurs at an early stage in CML pathogenesis and probably influences the clinical behavior of the disease.

Background and Objectives: The role of hematopoietic chimerism after allogeneic stem cell transplantation (SCT) for acute leukemia remains controversial. We studied the relationship between hematopoietic chimerism and several prognostic variables on the outcome of SCT in patients with acute leukemia., Design and Methods: Chimerism was determined by a semiquantitative method, based on polymerase chain reaction (PCR) amplification of variable number tandem repeat (VNTR) minisatellites, in 133 consecutive patients who underwent allogeneic SCT for acute leukemia (68 myeloid, 58 lymphoid and 7 biphenotypic), all receiving a myeloablative conditioning regimen., Results: The median follow-up for the surviving patients was 44.8 months (range: 12.0-129.0). Recipient hematopoiesis (mixed chimerism, MC) was detected in 40 cases (30.1%). Two types of patients could be distinguished in this MC group: 29 with increasing MC and 9 with decreasing MC. The remaining 93 cases maintained complete donor chimerism (CC) over the whole follow-up period. Patients with increasing MC showed a significantly higher (p<0.001) rate of relapse (93.1%) and death (89.7%) in comparison to both those with CC (26.9% relapse, 44.1% dead) or decreasing MC (11.1% relapse, 44.4% dead). The detection of increasing MC preceded relapse by a median of 74 days (range: 5-434) and was significantly related with the absence of chronic graft-versus-host disease. Univariate and multivariate analysis confirmed that chimerism was the most significant variable involved in relapse, leukemia-free survival and overall survival after SCT., Interpretation and Conclusions: These results demonstrate that sequential determination of chimerism allows the prediction of relapse and death after SCT for acute leukemia. The interval between detection of increasing MC and relapse may permit timely implementation of therapeutic measures.