Leukemia
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Latest Research Publications
Childhood Leukaemia
Acute Lymphocytic Leukemia: (ALL)
Acute Myeloid Leukemia: (AML)
Chronic Lymphocytic Leukemia: (CLL)
Chronic Myeloid Leukemia: (CML)
Hairy Cell Leukemia

Information Patients and the Public (13 links)


Information for Health Professionals / Researchers (4 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Ibrahem WN, Hasony HJ, Hassan JG
Human parvovirus B19 in childhood acute lymphoblastic leukaemia in Basrah.
J Pak Med Assoc. 2014; 64(1):9-12 [PubMed] Related Publications
OBJECTIVE: To investigate the association of human parvovirus B19 infection with the onset of acute lymphoblastic leukaemia and its effect on TEL-AML-1 fusion gene and the presence of mutant P53.
METHODS: The case-control study was conducted at Basrah Hospital for Paediatrics and Gynaecology, Basrah, Iraq, from May 2009 to April 2010. A total of 100 blood samples were collected from 40 newly diagnosed cases and 60 healthy children to serve as control matched by age and gender. Human parvovirus B19-IgG and anti-P53 antibody were detected by enzyme-linked immunosorbent assay and TEL-AML-1 fusion gene was detected by reverse transcriptase-polymerase chain reaction on extracted ribonucleic acid from fresh blood samples using specified primers. SPSS 15 was used for statistical analysis.
RESULTS: A higher proportion of human parvovirus B19-positive cases was found in leukaemic patients (n=19; 47.5%) compared to 12 (20%) in the control group (p<0.05). There was significant association between TEL-AML-1 translocation and human parvovirus-B19 infection as 10 (71.4%) of TEL-AML-1 translocation-positive cases had human parvovirus-B19 IgG. On the other hand, there was no association between such infections and P53 gene mutation in the patients.
CONCLUSION: Human parvovirus-B19 infection is common in the population, with higher prevalence among leukaemic patients with significant association between human parvovirus-B19 and TEL-AML-1 fusion gene in patients of acute lymphoblastic leukaemia.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Abdelmalak CA, Yahya RS, Elghannam DM, et al.
PRAME gene expression in childhood acute lymphoblastic leukemia: impact on prognosis.
Clin Lab. 2014; 60(1):55-61 [PubMed] Related Publications
BACKGROUND: The PRAME (preferentially expressed antigen of melanoma) gene is frequently overexpressed in a wide variety of malignant diseases, including acute myeloid leukemia (AML) and acute B-cell malignancies.
AIM: To study the expression of PRAME gene and clarify its prognostic impact on disease outcome.
METHODS: Screening for PRAME gene expression was assessed using real-time reverse transcriptase polymerase chain reaction in 55 pretreated ALL bone marrow samples.
RESULTS: PRAME positivity was found in 14 (31.3%) of 45 patients. No significant correlation could be observed between PRAME expression and clinical characteristics. Positive PRAME expressers had a statistically higher CR (p = 0.001), lower relapse (p = 0.02), lower mortality (p < 0.001), a trend towards lower Refractory disease (p = 0.10), and a statistically longer DFS and OS (p < 0.001, < 0.001, respectively) in comparison to negative PRAME expressers.
CONCLUSIONS: Our results suggested that PRAME was a predictor for better outcome, could be a useful target for immunotherapy, and might represent a candidate marker for the monitoring of minimal residual disease.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Zhang M, Zhao H, Shi XZ, et al.
Effects of DNAzymes and siRNA targeting AKT1 on the growth of human T leukemic cells.
Clin Lab. 2014; 60(1):1-8 [PubMed] Related Publications
BACKGROUND: AKT1 is a member of the serine/threoine AGC protein kinase family involved in cancer's metabolism, growth, proliferation, and survival. It is a potential target for cancer gene therapy.
METHODS: In the present study, we used DNAzyme and siRNA technology to inhibit AKT1 expression and evaluated the effects of DNAzymes and siRNA as therapeutic agents to treat leukemic cells. We designed two AKT1 specific DNAzymes (DRz1 and DRz2) and siRNA to test their effects on the apoptosis of leukemic cells.
RESULTS: Here, we showed that DRz1 could down-regulate the expression of AKT1 in both mRNA and protein levels, hence significantly inhibiting growth and inducing apoptosis of Jurkat cells.
CONCLUSIONS: These results provide a significant insight into the potential anticarcinogenic action of DNAzyme against AKT1 which might be used as a valuable therapy to leukemia.

Related: AKT1


Lehnertz B, Pabst C, Su L, et al.
The methyltransferase G9a regulates HoxA9-dependent transcription in AML.
Genes Dev. 2014; 28(4):317-27 [PubMed] Article available free on PMC after 15/08/2014 Related Publications
Chromatin modulators are emerging as attractive drug targets, given their widespread implication in human cancers and susceptibility to pharmacological inhibition. Here we establish the histone methyltransferase G9a/EHMT2 as a selective regulator of fast proliferating myeloid progenitors with no discernible function in hematopoietic stem cells (HSCs). In mouse models of acute myeloid leukemia (AML), loss of G9a significantly delays disease progression and reduces leukemia stem cell (LSC) frequency. We connect this function of G9a to its methyltransferase activity and its interaction with the leukemogenic transcription factor HoxA9 and provide evidence that primary human AML cells are sensitive to G9A inhibition. Our results highlight a clinical potential of G9A inhibition as a means to counteract the proliferation and self-renewal of AML cells by attenuating HoxA9-dependent transcription.

Related: Acute Myeloid Leukemia (AML) HOXA9 gene


Carter BZ, Mak PY, Mak DH, et al.
Synergistic targeting of AML stem/progenitor cells with IAP antagonist birinapant and demethylating agents.
J Natl Cancer Inst. 2014; 106(2):djt440 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
BACKGROUND: Acute myeloid leukemia (AML) therapy has limited long-term efficacy because patients frequently develop disease relapse because of the inability of standard chemotherapeutic agents to target AML stem/progenitor cells. Here, we identify deregulated apoptotic components in AML stem/progenitor cells and investigate the individual and combinatorial effects of the novel inhibitor of apoptosis (IAP) protein antagonist and second mitochondrial-derived activator of caspases (SMAC) mimetic birinapant and demethylating epigenetic modulators.
METHODS: Protein expression was measured by reversed-phase protein array in AML patient (n = 511) and normal (n = 21) samples and by western blot in drug-treated cells. The antileukemic activity of birinapant and demethylating agents was assessed in vitro and in an in vivo AML mouse xenograft model (n = 10 mice per group). All statistical tests were two-sided.
RESULTS: Compared with bulk AML cells, CD34(+)38(-) AML stem/progenitors expressed increased cIAP1 and caspase-8 levels and decreased SMAC levels (one-way analysis of variance followed by Tukey's multiple comparison test, P < .001). Birinapant induced death receptor-/caspase-8-mediated apoptosis in AML cells, including in AML stem/progenitor cells, but not in normal CD34(+) cells. Demethylating agents modulated extrinsic apoptosis pathway components and, when combined with birinapant, were highly synergistic in vitro (combination index < 1), and also more effective in vivo (P < .001, by Student t test, for the median survival of birinapant plus 5-azacytadine vs birinapant alone or vs controls).
CONCLUSIONS: cIAP1, SMAC, and caspase-8 appear to play a role in AML stem cell survival, and synergistic targeting of these cells with birinapant and demethylating agents shows potential utility in leukemia therapy.

Related: Azacitidine Acute Myeloid Leukemia (AML)


Shlush LI, Zandi S, Mitchell A, et al.
Identification of pre-leukaemic haematopoietic stem cells in acute leukaemia.
Nature. 2014; 506(7488):328-33 [PubMed] Related Publications
In acute myeloid leukaemia (AML), the cell of origin, nature and biological consequences of initiating lesions, and order of subsequent mutations remain poorly understood, as AML is typically diagnosed without observation of a pre-leukaemic phase. Here, highly purified haematopoietic stem cells (HSCs), progenitor and mature cell fractions from the blood of AML patients were found to contain recurrent DNMT3A mutations (DNMT3A(mut)) at high allele frequency, but without coincident NPM1 mutations (NPM1c) present in AML blasts. DNMT3A(mut)-bearing HSCs showed a multilineage repopulation advantage over non-mutated HSCs in xenografts, establishing their identity as pre-leukaemic HSCs. Pre-leukaemic HSCs were found in remission samples, indicating that they survive chemotherapy. Therefore DNMT3A(mut) arises early in AML evolution, probably in HSCs, leading to a clonally expanded pool of pre-leukaemic HSCs from which AML evolves. Our findings provide a paradigm for the detection and treatment of pre-leukaemic clones before the acquisition of additional genetic lesions engenders greater therapeutic resistance.

Related: Acute Myeloid Leukemia (AML) NPM1 gene IDH2 gene IDH1 gene


Jung HA, Maeng CH, Park S, et al.
Prognostic factor analysis in core-binding factor-positive acute myeloid leukemia.
Anticancer Res. 2014; 34(2):1037-45 [PubMed] Related Publications
BACKGROUND: Acute myeloid leukemia (AML) cases with t(8;21) or inv(16) have a favorable outcome, but the associated prognoses are heterogeneous and complicated by additional molecular aberrations.
PATIENTS AND METHODS: Between January 2000 to December 2010, 67 patients were diagnosed with t(8;21) or inv(16) AML. We collected cytogenetic variables and analyzed treatment outcomes.
RESULTS: Among 67 patients, 51 (7.8%) had t(8;21) AML and 16 (2.4%) had inv(16) AML. Thrombocytopenia, and a high percentage of blasts in the peripheral blood and bone marrow were associated with poor overall survival. Twenty-five (49.0%) patients with t(8;21) had an additional chromosomal abnormality, while only six (37.5%) patients with inv(16) AML had a secondary chromosomal abnormality. The most common chromosomal abnormalities were deletion of the Y or X sex chromosomes.
CONCLUSION: Deletion of the Y chromosome may be a favorable prognostic factor in patients with core binding factor-positive AML.

Related: Chromosome 21 Chromosome 8 Cytarabine Idarubicin Acute Myeloid Leukemia (AML)


Tadmor T, Shvidel L, Goldschmidt N, et al.
Hodgkin's variant of Richter transformation in chronic lymphocytic leukemia; a retrospective study from the Israeli CLL study group.
Anticancer Res. 2014; 34(2):785-90 [PubMed] Related Publications
BACKGROUND: Richter syndrome (RS) is the development of an aggressive lymphoid malignancy, in chronic lymphocytic leukemia (CLL). Most are diffuse large B-cell lymphomas (DLBCL), however in 10-15% of RS, there is transformation to Hodgkin lymphoma, termed "Hodgkin variant" (HV). In the present retrospective study we summarize the Israeli experience with HV-RS, and analyze demographic data, relevant laboratory and clinical parameters, and outcome.
PATIENTS AND METHODS: We collected and analyzed data from 119 patients with RS from 12 Centers in Israel during 1996-2010 and identified 16 cases with "Hodgkin's variant".
RESULTS: The median age was 58 years, and 67% were males. The median time from CLL diagnosis to development of HV was 5.9 (range=0.8-11.9) years and the median survival was 39.5 months, compared to 9 months for the cases with RS-DLBCL.
CONCLUSION: Hodgkin variant appears to differ from DLBCL-RS and is clinically less aggressive. However, compared to de novo Hodgkin's lymphoma, HV-RS has a worse prognosis.

Related: Hodgkin's Lymphoma Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Suojanen J, Reunanen J, Ranta TM, et al.
Peptides against Mac-1 do not sufficiently target leukemia or lymphoma in vivo.
Anticancer Res. 2014; 34(2):645-50 [PubMed] Related Publications
BACKGROUND: β2 Integrins (cluster of differentiation-18, CD18) are expressed only by leukocytes and serve as cell surface receptors, being involved both in inside-out and outside-in signalling, and in cell movement. Therefore, they are interesting targets for therapeutic intervention. Phage display-derived inhibitory peptides against αMβ2 integrins (macrophage-1 antigen, Mac-1) have been found to be effective in preventing leukocyte movement in vitro and in vivo but little is known regarding their ability to target leukaemia and lymphoma in vivo.
MATERIALS AND METHODS: Athymic nude mice were inoculated with human THP-1 acute monocytic leukemia (AML-M5 variant), U937 diffuse histiocytic lymphoma, and OCI-AML-3 acute-myeloidic leukemia cells, and then treated with Mac-1-inhibiting peptides ADGACILWMDDGWCGAAG (DDGW) or CPCLLGCC fused with green fluorescent protein (LLG-GFP).
RESULTS: Mac-1-inhibiting DDGW peptide had no effect on leukemia and lymphoma burden in mice, and LLG-GFP fusion did not home to leukemia cells in vivo.
CONCLUSION: Although peptides against Mac-1 are promising drugs and diagnostic tools based on earlier experiments in inflammation they exhibit compromised biological avidity as a therapeutic and diagnostic means for leukaemia and lymphoma.

Related: Acute Myeloid Leukemia (AML)


Riches JC, Gribben JG
Hanging tough: CMV-specific CD8+ T cells in CLL.
Blood. 2014; 123(5):608-9 [PubMed] Related Publications
In this issue of Blood, te Raa et al report that cytomegalovirus (CMV)-specific CD8+ T-cell function is preserved in chronic lymphocytic leukemia (CLL), on a background of global T-cell dysfunction.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Kuiper RP, Waanders E
A RAG driver on the road to pediatric ALL.
Nat Genet. 2014; 46(2):96-8 [PubMed] Related Publications
Genomic aberrations affecting genes in B cell differentiation are hallmarks of B-precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1-positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism.


Azadmehr A, Hajiaghaee R, Mazandarani M
Induction of apoptosis and G2 /M cell cycle arrest by Scrophularia striata in a human leukaemia cell line.
Cell Prolif. 2013; 46(6):637-43 [PubMed] Related Publications
OBJECTIVES: Scrophularia striata Boiss (Scrophulariaceae) is a plant that grows in northeastern Iran; it has been used traditionally to treat various inflammatory disorders. This study was designed to investigate cytotoxic effects of S. striata extract, on the Jurkat human leukaemia cell line (T-cell leukaemia).
MATERIALS AND METHODS: Phytochemical assay by thin layer chromatography and 2, 2 diphenyl-1-picryl-hydrazyl were used to evaluate main compounds and antioxidant capacity of the plant extract, respectively. Its inhibitory effect on Jurkat cells was evaluated by MTT assay. In addition, cell cycle distribution and apoptotic cell death were evaluated by propidium iodide and annexin V-FITC/ propidium iodide staining.
RESULTS: These showed that the main components present in S. striata extract included flavonoids, phenolic compounds and phenyl propanoids. Treatment with extract was significantly cytotoxic to the tumour cell line. In addition, flow cytometry analysis indicated that S. striata extract induced cell cycle arrest in G2 /M phase and apoptosis of tumour cells.
CONCLUSIONS: Results of the study indicated that S. striata extract could inhibit leukaemia cell proliferation by inducing G2 /M phase arrest and apoptosis.

Related: Apoptosis


Furman RR, Sharman JP, Coutre SE, et al.
Idelalisib and rituximab in relapsed chronic lymphocytic leukemia.
N Engl J Med. 2014; 370(11):997-1007 [PubMed] Related Publications
BACKGROUND: Patients with relapsed chronic lymphocytic leukemia (CLL) who have clinically significant coexisting medical conditions are less able to undergo standard chemotherapy. Effective therapies with acceptable side-effect profiles are needed for this patient population.
METHODS: In this multicenter, randomized, double-blind, placebo-controlled, phase 3 study, we assessed the efficacy and safety of idelalisib, an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase, in combination with rituximab versus rituximab plus placebo. We randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. The primary end point was progression-free survival. At the first prespecified interim analysis, the study was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy.
RESULTS: The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P<0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P<0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P=0.02). Serious adverse events occurred in 40% of the patients receiving idelalisib and rituximab and in 35% of those receiving placebo and rituximab.
CONCLUSIONS: The combination of idelalisib and rituximab, as compared with placebo and rituximab, significantly improved progression-free survival, response rate, and overall survival among patients with relapsed CLL who were less able to undergo chemotherapy. (Funded by Gilead; ClinicalTrials.gov number, NCT01539512.).

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Rituximab (Mabthera)


Wong KF, Siu LL, Wong WS
Double minutes and MYC amplification: a combined May-Grunwald Giemsa and fluorescence in situ hybridization study.
Am J Clin Pathol. 2014; 141(2):280-4 [PubMed] Related Publications
OBJECTIVES: To report the demonstration of double minutes with MYC amplification in a case of myeloproliferative neoplasm with monocytosis in transformation by a combination of standard karyotyping and interphase and metaphase fluorescence in situ hybridization (FISH).
METHODS: To determine the lineage involvement, we applied combined morphology and an interphase FISH study using dual-color break-apart probes for MYC on peripheral blood film.
RESULTS: MYC amplification was demonstrated in both myeloid and monocytic cells but not lymphocytes. The MYC amplification was not associated with loss of MYC signals at the homologous 8q24 regions where the genes were located. Furthermore, the extent of MYC amplification has been shown to diminish as the granulocytes mature.
CONCLUSIONS: Combined morphology and FISH study has shown a pluripotent myeloid disorder and also an inverse relationship between cell maturity and MYC amplification.

Related: FISH


Dodon MD
Of mice, men, and HTLV-1.
Blood. 2014; 123(3):303-4 [PubMed] Related Publications
In this issue of Blood, Tezuka et al report the establishment of humanized mice infected by human T-cell leukemia virus type 1 (HTLV-1) that recapitulate adult T-cell leukemia (ATL)-like leukemic symptoms and display HTLV-1–specific adaptive immune responses.


Kode A, Manavalan JS, Mosialou I, et al.
Leukaemogenesis induced by an activating β-catenin mutation in osteoblasts.
Nature. 2014; 506(7487):240-4 [PubMed] Related Publications
Cells of the osteoblast lineage affect the homing and the number of long-term repopulating haematopoietic stem cells, haematopoietic stem cell mobilization and lineage determination and B cell lymphopoiesis. Osteoblasts were recently implicated in pre-leukaemic conditions in mice. However, a single genetic change in osteoblasts that can induce leukaemogenesis has not been shown. Here we show that an activating mutation of β-catenin in mouse osteoblasts alters the differentiation potential of myeloid and lymphoid progenitors leading to development of acute myeloid leukaemia with common chromosomal aberrations and cell autonomous progression. Activated β-catenin stimulates expression of the Notch ligand jagged 1 in osteoblasts. Subsequent activation of Notch signalling in haematopoietic stem cell progenitors induces the malignant changes. Genetic or pharmacological inhibition of Notch signalling ameliorates acute myeloid leukaemia and demonstrates the pathogenic role of the Notch pathway. In 38% of patients with myelodysplastic syndromes or acute myeloid leukaemia, increased β-catenin signalling and nuclear accumulation was identified in osteoblasts and these patients showed increased Notch signalling in haematopoietic cells. These findings demonstrate that genetic alterations in osteoblasts can induce acute myeloid leukaemia, identify molecular signals leading to this transformation and suggest a potential novel pharmacotherapeutic approach to acute myeloid leukaemia.

Related: Acute Myeloid Leukemia (AML) Signal Transduction


Fogelstrand L, Staffas A, Wasslavik C, et al.
Prognostic implications of mutations in NOTCH1 and FBXW7 in childhood T-ALL treated according to the NOPHO ALL-1992 and ALL-2000 protocols.
Pediatr Blood Cancer. 2014; 61(3):424-30 [PubMed] Related Publications
BACKGROUND: In children, T-cell acute lymphoblastic leukemia (T-ALL) has inferior prognosis compared with B-cell precursor ALL. In order to improve survival, individualized treatment strategies and thus risk stratification algorithms are warranted, ideally already at the time of diagnosis.
PROCEDURE: We analyzed the frequency and prognostic implication of mutations in NOTCH1 and FBXW7 in 79 cases of Swedish childhood T-ALL treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL-1992 and ALL-2000 protocols. In a subgroup of patients, we also investigated the functional relevance of NOTCH1 mutations measured as expression of the HES1, MYB, and MYC genes.
RESULTS: Forty-seven of the cases (59%) displayed mutations in NOTCH1 and/or FBXW7. There was no difference in overall (P = 0.14) or event-free survival (EFS) (P = 0.10) in patients with T-ALL with mutation(s) in NOTCH1/FBXW7 compared with patients with T-ALL without mutations in any of these genes. T-ALL carrying NOTCH1 mutations had increased HES1 and MYB mRNA expression (HES1 9.2 ± 1.9 (mean ± SEM), MYB 8.7 ± 0.8 (mean ± SEM)) compared to T-ALL with wild-type NOTCH1 (HES1 1.8 ± 0.7, MYB 5.1 ± 1.2, P = 0.02 and 0.008, respectively). In cases of T-ALL with high HES1 expression, improved overall (P = 0.02) and EFS (P = 0.028) was seen.
CONCLUSIONS: Increased NOTCH activity, reflected by increased HES1 expression, is associated with improved outcome in pediatric T-ALL, but its role as a diagnostic tool or a therapeutic target in future clinical treatment protocols remains to be elucidated.

Related: NOTCH1 gene FBXW7 gene


Boyer DF, Lindeman NI, Harris NL, Ferry JA
Peripheral T-cell lymphomas with cytotoxic phenotype in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma.
Am J Surg Pathol. 2014; 38(2):279-88 [PubMed] Related Publications
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is relatively common, and patients occasionally develop other neoplasms; however, patients who develop other types of lymphomas are rare. We encountered 3 patients with CLL/SLL (one 59-y-old man and 2 women aged 56 and 66 y) who developed T-cell lymphomas. Both women developed ALK anaplastic large cell lymphomas (ALCLs), whereas the man developed CD8 peripheral T-cell lymphoma, not otherwise specified. All 3 T-cell lymphomas expressed granzyme B and perforin, indicating a cytotoxic immunophenotype. In 1 case, the first presentation was a lymph nodal composite lymphoma. In the other 2 cases, the T-cell lymphomas arose <1 year after the diagnosis of CLL/SLL and were identified in a lymph node in one case and in the spleen in the other. The patient with a composite lymphoma (SLL/ALK ALCL) was treated and was free of disease at last follow-up, whereas the other 2 patients succumbed to their disease, 1 month and 7 months after the diagnosis of T-cell lymphoma. Peripheral T-cell lymphomas rarely occur in CLL/SLL patients. On the basis of our small series, those with a cytotoxic phenotype appear to be more common in this setting. The occurrence of ALK ALCL in 2 older patients was especially surprising and suggested that CLL/SLL may have played a role in the development of ALCL.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology


Hsi AC, Kreisel FH, Frater JL, Nguyen TT
Clinicopathologic features of adult T-cell leukemias/lymphomas at a North American tertiary care medical center: infrequent involvement of the central nervous system.
Am J Surg Pathol. 2014; 38(2):245-56 [PubMed] Related Publications
Human T-cell lymphotropic virus type 1 is associated with adult T-cell leukemia/lymphoma (ATLL). Published series of ATLLs seen at a United States medical institution are rare. We present the features of 4 ATLLs diagnosed at our North American tertiary care medical center from 1990 to 2012. Despite the absence of a history of origin from an endemic region, all our ATLLs demonstrated evidence of human T-cell lymphotropic virus type 1 infection. Central nervous system (CNS) involvement by ATLL was uncommon in our series, and represented only 1.6% (1/64) of all CNS B-cell or T-cell lymphomas diagnosed over a 20+ year period at our institution. Review of the medical literature reveals that the majority of CNS-involved ATLLs present with the lymphoma or acute subtype, and complete remission is difficult to achieve in these cases. CNS involvement frequently occurs with a systemic disease, which carries an aggressive clinical course with poor prognosis. In addition, CNS involvement by ATLL can be the initial presentation or seen with relapsed disease, can be the only site or be associated with other tissue sites of involvement, and may manifest with variable clinical signs/symptoms. Our retrospective study reveals that ATLLs are rare mature T-cell lymphomas in a native North American population, but the clinical and histopathologic features of ATLLs from this nonendemic region are similar to those seen from other endemic regions. Early recognition of these rare ATLLs involving uncommon sites, such as the CNS, will help optimize treatment for these infrequent mature T-cell lymphomas.

Related: Brain and Spinal Cord Tumours Cancer Screening and Early Detection


Papaemmanuil E, Rapado I, Li Y, et al.
RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia.
Nat Genet. 2014; 46(2):116-25 [PubMed] Article available free on PMC after 01/02/2015 Related Publications
The ETV6-RUNX1 fusion gene, found in 25% of childhood acute lymphoblastic leukemia (ALL) cases, is acquired in utero but requires additional somatic mutations for overt leukemia. We used exome and low-coverage whole-genome sequencing to characterize secondary events associated with leukemic transformation. RAG-mediated deletions emerge as the dominant mutational process, characterized by recombination signal sequence motifs near breakpoints, incorporation of non-templated sequence at junctions, ∼30-fold enrichment at promoters and enhancers of genes actively transcribed in B cell development and an unexpectedly high ratio of recurrent to non-recurrent structural variants. Single-cell tracking shows that this mechanism is active throughout leukemic evolution, with evidence of localized clustering and reiterated deletions. Integration of data on point mutations and rearrangements identifies ATF7IP and MGA as two new tumor-suppressor genes in ALL. Thus, a remarkably parsimonious mutational process transforms ETV6-RUNX1-positive lymphoblasts, targeting the promoters, enhancers and first exons of genes that normally regulate B cell differentiation.


Wang L, Cai SH, Xiong WY, et al.
Real-time quantitative polymerase chain reaction assay for detecting the eps8 gene in acute myeloid leukemia.
Clin Lab. 2013; 59(11-12):1261-9 [PubMed] Related Publications
BACKGROUND: Eps8 is a novel proto-oncogene related to the tumorigenesis, proliferation, metastasis, chemo-resistance, and prognosis of many human solid cancers. However, the function of Eps8 in acute myeloid leukemia (AML) is still unclear. Thus, this study aims to develop a real-time quantitative polymerase chain reaction (PCR) assay for Eps8 in AML.
METHODS: Eps8 was amplified and cloned into pMD18-T to generate the recombinant plasmid pMD18-T/Eps8 as standard DNA for the establishment of real-time quantitative PCR. This assay was used to detect the expression level of Eps8 in bone marrow samples from AML patients and healthy volunteers (control group).
RESULTS: The limit of detection achieved using this standard was 100 copies, which was 10 times more sensitive than that achieved using conventional PCR, indicating high sensitivity. Melting curve analysis demonstrated that the primers designed for the established real-time quantitative PCR assay were specific and available. The expression level of Eps8 in the AML patients increased compared with that in the control group (p = 0.013). Furthermore, the expression level of Eps8 showed significant correlation with the complete remission rate of AML patients to chemotherapy (p = 0.024).
CONCLUSIONS: The established assay is useful in detecting the expression level of Eps8. The results suggest that Eps8 may serve as a prognostic factor of responsiveness to chemotherapy in AML patients.

Related: Acute Myeloid Leukemia (AML)


Grever MR
Hairy cell: young living longer but not cured.
Blood. 2014; 123(2):150-1 [PubMed] Related Publications
In this issue of Blood, Rosenberg et al provide a detailed retrospective description of the long-term outcome of young patients with a diagnosis of hairy cell leukemia treated with cladribine.

Related: Cladribine Hairy Cell Leukemia HCL - Molecular Biology


Roe JS, Vakoc CR
C/EBPα: critical at the origin of leukemic transformation.
J Exp Med. 2014; 211(1):1-4 [PubMed] Article available free on PMC after 13/07/2014 Related Publications
Acute myeloid leukemia (AML) is a hematopoietic malignancy characterized by clonal expansion of myeloid progenitor cells. A major mechanistic theme in AML biology is the extensive collaboration among fusion oncoproteins, transcription factors, and chromatin regulators to initiate and sustain a transformed cellular state. A new study in this issue describes how the C/EBPα transcription factor is crucial for the initiation of AML induced by MLL fusion oncoproteins, but is entirely dispensable for the maintenance of established disease. These observations provide a unique glimpse into the pioneer round of regulatory events that are critical at the origin of AML formation. Furthermore, this study implies the existence of oncogene-induced positive feedback loops capable of bypassing the continuous need for certain regulators to propagate disease.

Related: Acute Myeloid Leukemia (AML)


Mushtaq N, Fadoo Z, Naqvi A
Childhood acute lymphoblastic leukaemia: experience from a single tertiary care facility of Pakistan.
J Pak Med Assoc. 2013; 63(11):1399-404 [PubMed] Related Publications
OBJECTIVE: To evaluate the demographic features, outcome and prognostic factors seen in children with acute lymphoplastic leukaemia at a tertiary care hospital.
METHODS: The retrospective descriptive study was conducted at Aga Khan University Hospital, Karachi, comprising data related to children below 15 years of age and treated between January 1997 and December 2006. Kaplan Meir survival curves were used to describe overall and event-free survival rates. Cox Proportional Hazards model was used to describe factors associated with death and relapse. SPSS 16 was the main statistical tool.
RESULTS: Of the total 121 children diagnosed with the condition, 79 (65.3%) were males; 86 (71.1%) patients were between 1-9 years of age; Immunophenotyping was done in 99 (81.81%) patients: 86 (87%) cases had precursor B and 13 (13.13%) had precursor T. Of the total, 106 (87.6%) patients opted for treatment, while 15 (11.6%) were lost to follow-up. Besides, 26 (21.7%) patients had at least one relapse; the most common site being bone marrow in 13 (50%) followed by central nervous system in 9 (36.6%). There were 20 (16.5%) deaths in the sample. Infection was the most frequent cause of death. The event-free survival and overall survival was 63% (n = 76) and 65% (n = 79) respectively.
CONCLUSION: Through the clinical characteristics of children with acute lymphoblastic leukamia were similar to those reported in literature, the outcomes were inferior. The high rate of infections and relapse warrant better supportive care and risk-based approach.

Related: Acute Lymphocytic Leukemia (ALL) Childhood Acute lymphoblastic leukaemia (ALL) ALL - Molecular Biology


Dong H, Dai H, Hu X, et al.
The (1->6)-β-glucan moiety represents a cross-reactive epitope of infection-induced malignancy surveillance.
J Immunol. 2014; 192(3):1302-12 [PubMed] Related Publications
Exposure to pathogen-associated molecular patterns (PAMPs) by vaccination or infection is known to have beneficial effects on neoplastic diseases, although the underlying molecular mechanisms are so far unclear. In this article, we report that Abs against (1→6)-β-d-glucan, a typical microbial PAMP and a major target for high titer circulating natural Abs in healthy human subjects, cross-recognize a novel tumor-associated carbohydrate Ag on cancer cells. The (1→6)-β-glucan cross-reactive moiety is immunologically dominant in tumor cells, as C57BL/6 mice harboring EL-4 solid tumors produced anti-(1→6)-β-glucan Abs and the titer of which significantly correlated with enhanced survival and smaller tumor burden. Moreover, the (1→6)-β-glucan-specific Abs exhibited potent tumoricidal activities in vitro. C57BL/6 mice immunized with Candida albicans produced protective immunity against inoculated EL-4 tumors, which was attributed to the formation of (1→6)-β-glucan-specific Abs. Importantly, (1→6)-β-glucan-specific Abs significantly prolonged the survival and reduced the tumor size in mice inoculated with EL-4 tumors. Our results demonstrate that the (1→6)-β-glucan cross-reactive moiety represents a focal point between infection immunity and cancer surveillance, and natural Abs against this epitope may contribute to the first-line antitumor surveillance in humans. Our data also provide important explanation for the long-observed relationship between feverish infection and concurrent remission from cancer.


Medeiros BC, Othus M, Estey EH, et al.
Unsuccessful diagnostic cytogenetic analysis is a poor prognostic feature in acute myeloid leukaemia.
Br J Haematol. 2014; 164(2):245-50 [PubMed] Related Publications
Chromosome banding analysis is the gold standard method for the identification of recurrent cytogenetic abnormalities in acute myeloid leukaemia (AML). It allows stratification of AML patients into subgroups with distinct responses to therapy and survival. Unfortunately, a variety of issues hamper cytogenetic evaluation in c. 10% of cases [unsuccessful cytogenetics (UC)] and the outcome of these patients is poorly understood. To better define the significance of UC in patients with AML, we compared the baseline characteristics and the prognostic impact of 94 (6%) patients, whose standard metaphase analysis yielded unacceptable results, to the remaining 1403 AML patients with successful cytogenetic analysis treated on successive Southwestern Oncology Group protocols. The incidence of UC increased with age, with peak incidence in patients older than 60 years. These patients had a lower response rate to induction chemotherapy (complete remission rate of 43%) and dismal 5-year survival rates (16%), which was especially poor in patients older than 60 years (<5%). The complete remission and survival rates were similar to those seen in patients with unfavourable karyotype. The early death rate was not increased. These results suggest that UC increases with age and predict for poor outcomes, similar to the outcomes of patients with unfavourable karyotype.

Related: Acute Myeloid Leukemia (AML)


Deininger MW, Kopecky KJ, Radich JP, et al.
Imatinib 800 mg daily induces deeper molecular responses than imatinib 400 mg daily: results of SWOG S0325, an intergroup randomized PHASE II trial in newly diagnosed chronic phase chronic myeloid leukaemia.
Br J Haematol. 2014; 164(2):223-32 [PubMed] Related Publications
The standard dose of imatinib for newly diagnosed patients with chronic phase chronic myeloid leukaemia (CP-CML) is 400 mg daily (IM400), but the optimal dose is unknown. This randomized phase II study compared the rates of molecular, haematological and cytogenetic response to IM400 vs. imatinib 400 mg twice daily (IM800) in 153 adult patients with CP-CML. Dose adjustments for toxicity were flexible to maximize retention on study. Molecular response (MR) at 12 months was deeper in the IM800 arm (4-log reduction of BCR-ABL1 mRNA: 25% vs. 10% of patients, P = 0·038; 3-log reduction: 53% vs. 35%, P = 0·049). During the first 12 months BCR-ABL1 levels in the IM800 arm were an average 2·9-fold lower than in the IM400 arm (P = 0·010). Complete haematological response was similar, but complete cytogenetic response was higher with IM800 (85% vs. 67%, P = 0·040). Grade 3-4 toxicities were more common for IM800 (58% vs. 31%, P = 0·0007), and were most commonly haematological. Few patients have relapsed, progressed or died, but both progression-free (P = 0·048) and relapse-free (P = 0·031) survival were superior for IM800. In newly diagnosed CP-CML patients, IM800 induced deeper MRs than IM400, with a trend for improved progression-free and overall survival, but was associated with more severe toxicity.

Related: Imatinib (Glivec)


Reikvam H, Tamburini J, Skrede S, et al.
Antileukaemic effect of PI3K-mTOR inhibitors in acute myeloid leukaemia-gene expression profiles reveal CDC25B expression as determinate of pharmacological effect.
Br J Haematol. 2014; 164(2):200-11 [PubMed] Related Publications
Acute myeloid leukaemia (AML) is a heterogeneous malignancy. Intracellular signalling through the phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) pathway is important for regulation of cellular growth and metabolism, and inhibitors of this pathway is considered for AML treatment. Primary human AML cells, derived from 96 consecutive adult patients, were examined. The effects of two mTOR inhibitors (rapamycin, temsirolimus) and two PI3K inhibitors (GDC-0941, 3-methyladenine) were studied, and we investigated cytokine-dependent proliferation, regulation of apoptosis and global gene expression profiles. Only a subset of patients demonstrated strong antiproliferative effects of PI3K-mTOR inhibitors. Unsupervised hierarchical clustering analysis identified two main clusters of patients; one subset showing weak or absent antiproliferative effects (59%) and another group showing a strong growth inhibition for all drugs and concentrations examined (41%). Global gene expression analyses showed that patients with AML cell resistance against PI3K-mTOR inhibitors showed increased mRNA expression of the CDC25B gene that encodes the cell cycle regulator Cell Division Cycle 25B. The antileukaemic effect of PI3K-Akt-mTOR inhibition varies between patients, and resistance to these inhibitors is associated with the expression of the cell cycle regulator CDC25B, which is known to crosstalk with the PI3K-Akt-mTOR pathway and mediate rapamycin resistance in experimental models.

Related: Cytokines Acute Myeloid Leukemia (AML) Signal Transduction


Navada SC, Steinmann J, Lübbert M, Silverman LR
Clinical development of demethylating agents in hematology.
J Clin Invest. 2014; 124(1):40-6 [PubMed] Article available free on PMC after 01/01/2015 Related Publications
The term epigenetics refers to the heritable changes in gene expression that are not associated with a change in the actual DNA sequence. Epigenetic dysregulation is linked to the pathogenesis of a number of malignancies and has been studied extensively in myelodysplastic syndromes and acute myeloid leukemia. DNA methylation is frequently altered in cancerous cells and likely results in transcriptional silencing of tumor suppressor genes. Re-expression of these genes by inhibition of the DNA methyltransferases has been successful in the treatment of benign and malignant disease. In this Review, we discuss the clinical development of demethylating agents in hematology, with a focus on azacitidine and decitabine.

Related: Azacitidine Acute Myeloid Leukemia (AML)


van den Broek EC, Liu L, Posthuma EF, et al.
Increased risk of chronic lymphocytic leukaemia among cancer survivors in the Netherlands: increased detection, causal factors or both?
Ann Hematol. 2014; 93(1):157-62 [PubMed] Related Publications
We assessed the risk of chronic lymphocytic leukaemia (CLL) following earlier primary malignancies (EPM) to explore the extent and determinants of this risk. We used the Netherlands Cancer Registry data of 1,313,232 cancer survivors who were at risk to be subsequently diagnosed with CLL between 1989 and 2008. Cancer survivors were categorized based on gender, age, time since diagnosis of EPM and type of EPM. CLL was regarded synchronous when diagnosed within 3 months after diagnosis of EPM; metachronous CLLs were those diagnosed later. Overall, we found that cancer survivors had a 90 % higher risk to be diagnosed with CLL than the general population. In the first year after diagnosis, we found a more than four-fold increased risk of CLL (standardized incidence ratio (SIR), 4.4; 95 % confidence interval (CI), 4.1-4.8); however, no increased risk was observed after excluding synchronous cases. After 1 year, the excess risk of subsequent CLL ranged from 1.2 to 1.8. An increased risk for metachronous CLL was found in prostate (SIR 1.3; 95 % CI 1.1-1.5) and squamous cell skin cancer survivors (SIR 2.3; 95 % CI 1.9-2.7). Intensive clinical checkups after/around diagnosis of the EPM seemed to be the main cause for the increased risk of CLL among cancer survivors. However, possible shared risk factors between prostate cancer and CLL and skin cancer and CLL cannot be excluded. Further clinical research aimed at CLL as subsequent primary malignancy (SPM) is warranted to elucidate possible shared biological and predisposing risk factors.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Cancer Prevention and Risk Reduction Children's Cancer Web: Home Page Prostate Cancer Skin Cancer


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