Author Correction: Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
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Published Erratum↗
Biomedical subjects
Martin S Tallman
Publications and source records attributed to Martin S Tallman.
Contrasting roles of histone 3 lysine 27 demethylases in acute lymphoblastic leukaemia.
T-cell acute lymphoblastic leukaemia (T-ALL) is a haematological malignancy with a dismal overall prognosis, including a relapse rate of up to 25%, mainly because of the lack of non-cytotoxic targeted therapy options. Drugs that target the function of key epigenetic factors have been approved in the context of haematopoietic disorders, and mutations that affect chromatin modulators in a variety of leukaemias have recently been identified; however, 'epigenetic' drugs are not currently used for T-ALL treatment. Recently, we described that the polycomb repressive complex 2 (PRC2) has a tumour-suppressor role in T-ALL. Here we delineated the role of the histone 3 lysine 27 (H3K27) demethylases JMJD3 and UTX in T-ALL. We show that JMJD3 is essential for the initiation and maintenance of T-ALL, as it controls important oncogenic gene targets by modulating H3K27 methylation. By contrast, we found that UTX functions as a tumour suppressor and is frequently genetically inactivated in T-ALL. Moreover, we demonstrated that the small molecule inhibitor GSKJ4 (ref. 5) affects T-ALL growth, by targeting JMJD3 activity. These findings show that two proteins with a similar enzymatic function can have opposing roles in the context of the same disease, paving the way for treating haematopoietic malignancies with a new category of epigenetic inhibitors.
Animals↗
Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer.
BACKGROUND: The prognosis for women with primary breast cancer and 10 or more involved axillary lymph nodes is poor. High-dose chemotherapy with autologous hematopoietic stem-cell transplantation has been reported to be effective in the adjuvant setting for patients at high risk for relapse. METHODS: We randomly assigned 540 female patients with primary breast cancer and at least 10 involved ipsilateral axillary lymph nodes to receive either six cycles of adjuvant chemotherapy with cyclophosphamide, doxorubicin, and fluorouracil (CAF) or the same adjuvant chemotherapy followed by high-dose chemotherapy with cyclophosphamide and thiotepa and autologous hematopoietic stem-cell transplantation. RESULTS: Among the 511 eligible patients, there was no significant difference in disease-free survival, overall survival, or the time to recurrence between those who received CAF alone and those who received CAF plus high-dose chemotherapy and stem-cell transplantation. Among 417 patients fulfilling strict eligibility criteria, the time to recurrence was longer for patients who underwent stem-cell transplantation than for those who received CAF alone. In the transplantation group, nine patients died of transplantation-related complications and a myelodysplastic syndrome or acute myeloid leukemia developed in nine. CONCLUSIONS: The addition of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation to six cycles of adjuvant chemotherapy with CAF may reduce the risk of relapse but does not improve the outcome among patients with primary breast cancer and at least 10 involved axillary lymph nodes. Conventional-dose adjuvant chemotherapy remains the standard of care for such patients.
Adult↗
Activation of protein kinase C delta by all-trans-retinoic acid.
All-trans-retinoic acid (RA) is a potent inhibitor of leukemia cell proliferation and induces differentiation of acute promyelocytic leukemia cells in vitro and in vivo. For RA to induce its biological effects in target cells, binding to specific retinoic acid nuclear receptors is required. The resulting complexes bind to RA-responsive elements (RAREs) in the promoters of RA-inducible genes to initiate gene transcription and to generate protein products that mediate the biological effects of RA. In this report, we provide evidence that a member of the protein kinase C (PKC) family of proteins, PKC delta, is activated during RA treatment of the NB-4 and HL-60 acute myeloid leukemia cell lines as well as the MCF-7 breast cancer cell line. Such RA-dependent phosphorylation was also observed in primary acute promyelocytic leukemia cells and resulted in activation of the kinase domain of PKC delta. In studies aimed at understanding the functional relevance of PKC delta in the induction of RA responses, we found that pharmacological inhibition of PKC delta (but not of other PKC isoforms) diminished RA-dependent gene transcription via RAREs. On the other hand, overexpression of a constitutively active form of the kinase strongly enhanced RA-dependent gene transcription via RAREs. Gel shift assays and chromatin immunoprecipitation studies demonstrated that PKC delta associated with retinoic acid receptor-alpha and was present in an RA-inducible protein complex that bound to RAREs. Pharmacological inhibition of PKC delta activity abrogated the induction of cell differentiation and growth inhibition of NB-4 blast cells, demonstrating that its function is required for such effects. Altogether, our data provide strong evidence that PKC delta is activated in an RA-dependent manner and plays a critical role in the generation of the biological effects of RA in malignant cells.
Cell Differentiation↗
New developments in antibody therapy for acute myeloid leukemia.
In the past three decades, improvements in the treatment of acute myeloid leukemia (AML) have increased survival in patients younger than 55 years without significant survival impact in older individuals. Unfortunately, many patients, regardless of age at diagnosis, will eventually die from their disease. Advances in the development of targeted therapies have proven beneficial in chronic myeloid leukemia and lymphoma. Gemtuzumab ozogamicin (GO; Mylotarg, Wyeth-Ayerst, St Davids, PA), a monoclonal antibody conjugated to calicheamicin, targets the CD33 antigen found on the surface of more than 80% of AML leukemic blasts. GO is approved for relapsed disease in patients older than 60 years, but is being evaluated in combination with chemotherapy, in the setting of hematopoietic stem cell transplant, and in high-risk myelodysplasia.
Acute Disease↗
Comparison of interphase FISH and metaphase cytogenetics to study myelodysplastic syndrome: an Eastern Cooperative Oncology Group (ECOG) study.
Cytogenetic analysis can be important in determining the prognosis and diagnosis of a number of hematological disorders, including myelodysplastic syndromes (MDS). Here, we compared metaphase chromosomal analyses on bone marrow aspirates from MDS patients with interphase fluorescence in situ hybridization (FISH) using probes specific for chromosomes nos. 5, 7, 8, 11, 13 and 20. Forty-three patients enrolled in ECOG protocol E1996 for low risk MDS and five patients enrolled in ECOG protocol E3996 for high risk MDS were studied by both metaphase chromosomal analysis and interphase FISH. Excluding those with a clonal loss of the Y chromosome, an abnormal clone was detected by cytogenetic analysis in 18 of 48 samples (37.5%). In comparison, our FISH panel detected an abnormal clone in 17 of 48 samples (35.4%). Twenty-nine of 30 samples with apparently normal karyotypes, including those with a missing Y chromosome, were also normal by our FISH panel. One patient had an occult deletion of chromosome 11 that was detected by FISH. These results indicate that around 60% of patients with MDS do not have abnormalities that are detectable by either chromosomal or FISH studies. In addition, it appears that interphase FISH studies are nearly as sensitive as cytogenetic analyses and can be a useful tool in studying bone marrow aspirates where cytogenetic analysis is not possible.
Antineoplastic Agents↗
Splenectomy and treatments of historical interest.
Hairy-cell leukaemia (HCL) was initially described as a distinct clinical entity in 1958. Various types of therapy have been evaluated since this initial description and several are currently important only for historical comparison. Hairy-cell leukaemia serves as an example of rapid progress in the development of effective therapeutic strategies. Splenectomy was the first effective treatment because it resulted in an improvement in cytopenias and relief from symptomatic splenomegaly. However, complete remission of the disease was observed only very rarely. Splenectomy was considered an appropriate initial therapy from the 1950s to the early 1980s, although no randomized controlled studies have ever shown improved survival with this approach. In the early 1980s, more effective treatments were identified, initially interferon-alpha, then the purine analogues 2-deoxycoformycin and 2-chlorodeoxyadenosine (2-CdA). These types of therapy have been so effective that most previous treatments are now obsolete. Although the purine analogues result in sustained remissions in the majority of patients, a relatively small percentage of patients relapse and require other types of therapy. Splenectomy may be necessary in some instances. In this chapter the role of splenectomy is reviewed and other types of therapy of historical interest are presented.
Antineoplastic Agents↗
Retinoic acid syndrome: manifestations, pathogenesis, and treatment.
All-trans retinoic acid (ATRA) is a potent differentiation agent that is effective therapy in acute promyelocytic leukaemia. Although ATRA is generally well tolerated, some patients develop retinoic acid syndrome. This syndrome is manifested by unexplained fever, weight gain, respiratory distress, interstitial pulmonary infiltrates, pleural and pericardial effusion, episodic hypotension, and acute renal failure. However, if identified early enough, effective therapy can be administered. This chapter discusses the clinical aspects and pathogenesis of retinoic acid syndrome.
Chemotaxis, Leukocyte↗
All-trans retinoic acid in acute promyelocytic leukaemia.
The vitamin A derivative, all-trans retinoic acid (ATRA), induces differentiation of leukaemic promyelocytes in patients with acute promyelocytic leukaemia (APL). As a result, the majority of patients achieve complete remission either with ATRA alone or with combined ATRA and chemotherapy. The most important complication is the retinoic acid syndrome, which is usually successfully treated with the early administration of dexamethasone. Prospective randomized trials have shown that ATRA is better than conventional chemotherapy in newly diagnosed patients, that ATRA combined with chemotherapy confers an advantage with respect to relapse rate, compared to ATRA alone for induction followed by chemotherapy for consolidation, and that maintenance therapy with ATRA or ATRA plus low-dose chemotherapy is beneficial. The presence of adverse prognostic factors, including older age, presenting white blood cell count and platelet count, expression of CD56 and presence of mutations in the FLT3 gene, identify patients at risk for relapse for whom new strategies are needed.
Drug Resistance, Neoplasm↗
Long-term follow-up and potential for cure in acute promyelocytic leukaemia.
Acute promyelocytic leukaemia (APL) may be characterized simultaneously as the most potentially rapidly fatal human acute leukaemia if untreated, yet the most frequently cured acute leukaemia if promptly diagnosed and treated without delay. Co-operative group and single-institution studies which include large numbers of patients with relatively long follow-up demonstrate that, with all-trans retinoic acid (ATRA) plus anthracycline-based chemotherapy, the majority of newly-diagnosed patients appear cured of their disease. The 5-year disease-free survival rates range from 75 to 85%. Early death is still observed in approximately 10% of patients and remains a difficult obstacle to increasing the cure rate. Prognostic factors which identify patients at high risk for recurrence are becoming increasingly recognized. Older age (over age 55-60 years), elevated white blood cell count at presentation (higher than 5,000-10,000/microl), and expression of CD56 unfavourably influence outcome. The treatment of such patients remains a challenge, although it is important to note that APL is the only type of AML in which a significant proportion of older patients may be cured. Because more patients are cured of their disease, potential long-term consequences may become increasingly recognized. These include the emergence of extramedullary disease, the development of secondary myelodysplasia or acute myeloid leukaemia and the potential for late-onset cardiac toxicity.
Antineoplastic Agents↗
Bleeding in acute leukemia.
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Acute Disease↗
Chronic myeloid leukemia following therapy with imatinib mesylate (Gleevec). Bone marrow histopathology and correlation with genetic status.
We evaluated bone marrow pathologic features and cytogenetic and molecular genetic status of 13 patients with interferon-resistant, chronic-phase chronic myeloid leukemia (CML), treated with imatinib mesylate (Gleevec). All had morphologic evidence of CML in the blood and bone marrow and were positive for bcr-abl by reverse transcriptase-polymerase chain reaction, fluorescence in situ hybridization (FISH), or both. Follow-up marrow biopsies, interphase FISH for bcr-abl, and conventional cytogenetics were performed at 3-month intervals (up to 24 months) after therapy initiation. All patients exhibited a reduction in bone marrow cellularity with decreases in myeloid/erythroid ratios at 3 to 6 months after therapy. The percentage of bcr-abl-positive cells by FISH decreased in all patients (pretherapy median, 73%; 3 months median, 47%). Cytogenetic and FISH data defined 2 groups after 6 months of follow-up: 5 patients became negative for bcr-abl by FISH; 8 remained positive, 4 of whom developed signs of clonal cytogenetic evolution. Patients who became negative for bcr-abl had no morphologic evidence of CML at 15 to 24 months of follow-up, whereas patients who remained positive redeveloped morphologic features of CML as cellularity increased. Some bcr-abl-positive patients showed signs of progression, including 2 patients who developed myeloid blast phase. Although all patients demonstrated an initial decrease in bone marrow cellularity after imatinib mesylate therapy, continued follow-up showed that histopathologic findings correlated with genetic response.
Antineoplastic Agents↗
Acute promyelocytic leukaemia:a review.
Acute promyelocytic leukaemia (APL) is characterised by the fusion gene transcript PML-RAR-alpha and is now the most frequently curable acute leukaemia in adults if promptly diagnosed and adequately treated. The clinical presentation is associated with a haemorrhagic diathesis and the blasts almost always have Auer rods. Poor prognostic factors include older age, elevated white blood cell count, low platelet count, and CD56 expression. The introduction of all-trans retinoic acid (ATRA), which leads to the differentiation of leukaemic blasts into mature granulocytes has been the major breakthrough in the treatment of APL. Induction treatment with concurrent ATRA and chemotherapy leads to a rapid resolution of the characteristic life-threatening coagulopathy, high complete remission rates and excellent survival rates, compared to chemotherapy alone. However, treatment with ATRA is associated with the retinoic acid syndrome (RAS), which is a major toxicity and may lead to mortality. The role of cytarabine as a part of initial induction regimen remains unclear. After achievement of complete remission (CR), there is a definitive role of maintenance therapy with ATRA with or without low-dose chemotherapy. In relapsed patients, arsenic trioxide is considered the treatment of choice. However, the best postremission treatment for patients with second CR remains unknown. With the continued improvement in the field of stem cell transplantation, it may play an important role in the few patients with relapsed/refractory disease or those in second CR.
Adult↗
Biphenotypic acute leukemia with coexpression of CD79a and markers of myeloid lineage.
Acute leukemias demonstrating immunophenotypic features of more than 1 cell lineage are referred to as acute leukemias of ambiguous lineage in the new World Health Organization classification system. A subtype of leukemia of ambiguous lineage is biphenotypic acute leukemia in which the malignant cell population expresses markers of 2 different lineages, most commonly myeloid and either B- or T-lymphoid lineages. This entity has been defined by a scoring system proposed by the European Group for the Immunological Characterization of Acute Leukemias (EGIL), with various markers assigned a score of 2, 1, or 0.5 depending on their specificity for myeloid or lymphoid lineage. Those cases having a score greater than 2 for the myeloid and either the B- or T-lymphoid lineages are biphenotypic acute leukemia in this system. One marker, CD79a, has been so clearly associated with acute lymphoblastic leukemia (ALL) by some researchers that its expression in the presence of blast markers is considered indicative of B-ALL. We describe an unusual case of acute leukemia meeting the criteria for biphenotypic acute leukemia in which CD79a expression was observed in the blast population.
Aged↗
Quantitative real-time RT-PCR analysis of PML-RAR alpha mRNA in acute promyelocytic leukemia: assessment of prognostic significance in adult patients from intergroup protocol 0129.
The potential prognostic value of quantitative real-time reverse transcription-polymerase chain reaction (RT-PCR [qrtPCR]) measurements of PML-RAR alpha mRNA in acute promyelocytic leukemia was retrospectively assessed before treatment and at 3 posttreatment intervals in 123 patients on intergroup protocol 0129. The primary measure was the PML-RAR alpha(GAPDH) normalized quotient (NQ), that is, PML-RAR alpha mRNA copies divided by glyceraldehyde-3'-phosphate dehydrogenase (GAPDH) mRNA copies. Only samples with more than 2.5 x 10(5) copies of the housekeeping gene GAPDH mRNA (detection sensitivity exceeding 10(4)) were considered NQ evaluable. With RNA from low-density selected cells, paired peripheral blood (PB) and bone marrow samples (n = 140) had comparable NQs (P <.001). Before treatment, high NQ was associated with short-form PML-RAR alpha (P <.001), but not with white blood cell count or clinical outcome. Following treatment, NQ was lower in all-trans retinoic acid-induced complete remission (CR) than chemotherapy-induced CR (P =.018) and at first test after consolidation chemotherapy (P =.037). After consolidation chemotherapy, patients with NQ exceeding 10(-5) had 4.1-fold increased relapse risk (P =.008); however, 73% of patients who experienced relapse had NQ lower than 10(-5). In the follow-up period (FUP), any NQ exceeding 10(-5) and 10(-6) had 17.5-fold and 7.6-fold increased relapse risk, respectively (P <.001), while no gradation of relapse risk (approximately 18%) could be identified at NQ lower than 10(-6), including NQ(-). These results indicate that qrtPCR monitoring of PML-RAR alpha NQ can identify patients at high risk of relapse and suggest that clinically practical PB NQ monitoring at more frequent FUP intervals may improve predictive accuracy for relapse or continuing CR in patients with persistent, fluctuating minimal residual disease levels.
Adolescent↗
All-trans retinoic acid in acute promyelocytic leukemia: long-term outcome and prognostic factor analysis from the North American Intergroup protocol.
We previously reported a benefit for all-trans retinoic acid (ATRA) in both induction and maintenance therapy in patients with acute promyelocytic leukemia (APL). To determine the durability of this benefit and identify important prognostic factors, long-term follow-up of the North American Intergroup APL trial is reported. A total of 350 patients with newly diagnosed APL were randomized to either daunorubicin and cytarabine (DA) or ATRA for induction and then either ATRA maintenance or observation following consolidation chemotherapy. The complete remission (CR) rates were not significantly different between the ATRA and DA groups (70% and 73%, respectively). However, the 5-year disease-free survival (DFS) and overall survival (OS) were longer with ATRA than with DA for induction (69% vs 29% and 69% vs 45%, respectively). Based on both induction and maintenance randomizations, the 5-year DFS was 16% for patients randomized to DA and observation, 47% for DA and ATRA, 55% for ATRA and observation, and 74% for ATRA and ATRA. There was no advantage of either induction regimen among any subgroups when CR alone was considered. However, female sex, classical M3 morphology (vs the microgranular variant [M3v]), and treatment-white blood cell count (WBC) interaction (ATRA/WBC below 2 x 10(9)/L [2000/microL] best, DA/WBC above 2 x 10(9)/L worst) were each significantly associated with improved DFS (P <.05). Treatment with ATRA, WBC below 2 x 10(9)/L, and absence of bleeding disorder were each significantly associated with improved OS. Age more than 15 years, female sex, and treatment-morphology interaction (DA/M3v worst, ATRA best regardless of morphology) were each significantly associated with improved DFS based on maintenance randomization. The improvement in outcome with ATRA in APL was maintained with long-term follow-up.
Adolescent↗
A single, high dose of idarubicin combined with cytarabine as induction therapy for adult patients with recurrent or refractory acute lymphoblastic leukemia.
BACKGROUND: The majority of adult patients who are treated for lymphoblastic disease will either develop recurrent disease or will be refractory to their initial therapy. One option for patients with recurrent/refractory disease is to administer a reinduction regimen that employs a dose-intense combination of anthracycline and cytarabine. These salvage regimens are relatively distinct from the traditional vincristine/prednisone-based programs that are used typically as primary induction therapy. The authors studied a regimen that contained high-dose cytarabine and a single high dose of idarubicin as salvage induction therapy for patients with recurrent or refractory lymphoblastic disease. METHODS: Twenty-nine previously treated adult patients with recurrent or refractory acute lymphoblastic leukemia were treated with a new intensive regimen. Eight patients had primary refractory disease. Twenty-one patients had recurrent disease, and 16 of these patients developed recurrent disease while they were still receiving their primary therapy. The treatment regimen consisted of cytarabine 3.0 g/m(2) by 3-hour infusion daily for 5 days and idarubicin 40 mg/m(2) given as a single dose on Day 3. Filgrastim (granulocyte-colony stimulating factor) 5 microg/kg administered subcutaneously every 12 hours was started on Day 7 and was continued until the absolute neutrophil count was > 5000/microL. Response was assessed using standard criteria. RESULTS: There were 11 complete responses (38%; 95% confidence interval, 20-56%). Four patients subsequently underwent allogeneic bone marrow transplantation. Moderate but acceptable toxicity was observed given the severely myelosuppressive nature of the regimen. There was only one treatment-related death (3%). Two patients, both with significant prior exposure to anthracyclines, suffered reductions in left ventricular function to the 20-30% range during episodes of severe systemic infection. After recovery from infection, the ejection fraction in one patient improved to 50%. CONCLUSIONS: The authors conclude that this regimen has moderate activity and a relatively low incidence of mortality for this high-risk group of patients. This regimen may be most suitable for patients who can undergo potentially curative allogeneic bone marrow transplantation if they achieve a complete response.
Adult↗
Acute promyelocytic leukemia: evolving therapeutic strategies.
Acute promyelocytic leukemia (APL) is now the most curable subtype of acute myeloid leukemia in adults. All-trans retinoic acid (ATRA), which induces differentiation of the leukemic cells into mature granulocytes, represents the important advance. The incorporation of ATRA in induction results in a high complete remission rate, leads to rapid resolution of the characteristic life-threatening coagulopathy, and, most importantly, decreases the relapse rate compared with treatment with chemotherapy alone. However, ATRA is associated with unique toxicities not observed with conventional cytotoxic chemotherapy. A number of clinical trials have been performed to define the optimal role of ATRA in the treatment of patients. The therapeutic strategies have rapidly evolved as a result of both single institution and large cooperative group trials. Arsenic trioxide and stem cell transplantation are effective treatments for patients with APL who relapse after or are refractory to ATRA-based therapy. As experience with ATRA and arsenic trioxide in patients with APL accumulates, a number of important questions arise that need to be addressed.
Animals↗