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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).

McGill CM, Alba-Rodriguez EJ, Li S, et al.
Extracts of Devil's club (Oplopanax horridus) exert therapeutic efficacy in experimental models of acute myeloid leukemia.
Phytother Res. 2014; 28(9):1308-14 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a group of hematological malignancies defined by expanded clonal populations of immature progenitors (blasts) of myeloid phenotype in blood and bone marrow. Given a typical poor prognostic outlook, there is great need for novel agents with anti-AML activity. Devil’s club (Oplopanax horridus) is one of the most significant medicinal plants used among the indigenous people of Southeast Alaska and the coastal Pacific Northwest, with different linguistic groups utilizing various parts of the plant to treat many different conditions including cancer. Studies identifying medically relevant components in Devil’s club are limited. For this research study, samples were extracted in 70% ethanol before in vitro analysis, to assess effects on AML cell line viability as well as to study regulation of tyrosine phosphorylation and cysteine oxidation. The root extract displayed better in vitro anti-AML efficacy in addition to a noted anti-tyrosine kinase activity independent of an antioxidant effect. In vivo therapeutic studies using an immunocompetent murine model of AML further demonstrated that Devil’s club root extract improved the murine survival while decreasing immunosuppressive regulatory T cells and improving CD8+ T-cell functionality. This study defines for the first time an anti-AML efficacy for extracts of Devil’s club.

Related: Acute Myeloid Leukemia (AML) Signal Transduction

Bansode YV, Admane V, Goroshi M, Katria P
Plasma cell leukaemia a rare cause of disproportionate anaemia in a patient presenting as CKD.
J Assoc Physicians India. 2014; 62(3):271-3 [PubMed] Related Publications
The anaemia in patient of chronic kidney disease is commonly related to secondary erythropoietin deficiency. When the severity of anaemia is disproportionate and associated with other haematological abnormalities like thrombocytopenia, then primary haematological disorder and secondary renal involvement must be considered. Renal involvement is common in haematologic disorder like Multiple Myeloma. The diagnosis of haematological disorder may be missed. This is a case of chronic kidney disease with disproportionate severe anaemia with bleeding diasthesis which ultimately turned out to be plasma cell leukaemia.

Maude SL, Frey N, Shaw PA, et al.
Chimeric antigen receptor T cells for sustained remissions in leukemia.
N Engl J Med. 2014; 371(16):1507-17 [PubMed] Related Publications
BACKGROUND: Relapsed acute lymphoblastic leukemia (ALL) is difficult to treat despite the availability of aggressive therapies. Chimeric antigen receptor-modified T cells targeting CD19 may overcome many limitations of conventional therapies and induce remission in patients with refractory disease.
METHODS: We infused autologous T cells transduced with a CD19-directed chimeric antigen receptor (CTL019) lentiviral vector in patients with relapsed or refractory ALL at doses of 0.76×10(6) to 20.6×10(6) CTL019 cells per kilogram of body weight. Patients were monitored for a response, toxic effects, and the expansion and persistence of circulating CTL019 T cells.
RESULTS: A total of 30 children and adults received CTL019. Complete remission was achieved in 27 patients (90%), including 2 patients with blinatumomab-refractory disease and 15 who had undergone stem-cell transplantation. CTL019 cells proliferated in vivo and were detectable in the blood, bone marrow, and cerebrospinal fluid of patients who had a response. Sustained remission was achieved with a 6-month event-free survival rate of 67% (95% confidence interval [CI], 51 to 88) and an overall survival rate of 78% (95% CI, 65 to 95). At 6 months, the probability that a patient would have persistence of CTL019 was 68% (95% CI, 50 to 92) and the probability that a patient would have relapse-free B-cell aplasia was 73% (95% CI, 57 to 94). All the patients had the cytokine-release syndrome. Severe cytokine-release syndrome, which developed in 27% of the patients, was associated with a higher disease burden before infusion and was effectively treated with the anti-interleukin-6 receptor antibody tocilizumab.
CONCLUSIONS: Chimeric antigen receptor-modified T-cell therapy against CD19 was effective in treating relapsed and refractory ALL. CTL019 was associated with a high remission rate, even among patients for whom stem-cell transplantation had failed, and durable remissions up to 24 months were observed. (Funded by Novartis and others; CART19 ClinicalTrials.gov numbers, NCT01626495 and NCT01029366.).

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

Zahir MN, Masood N, Shabbir-Moosajee M
t(1:14) and trisomy 4 in a patient with concomitant leukaemias.
J Pak Med Assoc. 2014; 64(5):596-8 [PubMed] Related Publications
Cytogenetic abnormalities have long been recognized as the genetic basis of the occurrence of various malignancies. Specific cytogenetic abnormalities have shown to occur recurrently in particular subtypes of leukaemias and lymphomas. t(1;14) is an infrequently occurring recurrent chromosomal translocation that has been described in literature to be associated with haematological malignancies. Trisomy 4 is another rare genetic abnormality which has been reported in association with both acute myeloid and lymphoid leukaemias. The concomitant occurrence of a myeloid malignancy in association with a lymphoproliferative disorder is a distinctly unusual phenomenon. We report the case of a young patient with concomitant T-cell acute lymphoblastic leukaemia and acute myeloid leukaemia with a novel cytogenetic abnormality i.e. t(1;14) with trisomy 4. We believe this is the first reported case where a patient with two concomitant haematological malignancies, harboured this karyotype.

Related: Chromosome 4 Acute Myeloid Leukemia (AML)

Roberts KG, Li Y, Payne-Turner D, et al.
Targetable kinase-activating lesions in Ph-like acute lymphoblastic leukemia.
N Engl J Med. 2014; 371(11):1005-15 [PubMed] Article available free on PMC after 11/03/2015 Related Publications
BACKGROUND: Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is characterized by a gene-expression profile similar to that of BCR-ABL1-positive ALL, alterations of lymphoid transcription factor genes, and a poor outcome. The frequency and spectrum of genetic alterations in Ph-like ALL and its responsiveness to tyrosine kinase inhibition are undefined, especially in adolescents and adults.
METHODS: We performed genomic profiling of 1725 patients with precursor B-cell ALL and detailed genomic analysis of 154 patients with Ph-like ALL. We examined the functional effects of fusion proteins and the efficacy of tyrosine kinase inhibitors in mouse pre-B cells and xenografts of human Ph-like ALL.
RESULTS: Ph-like ALL increased in frequency from 10% among children with standard-risk ALL to 27% among young adults with ALL and was associated with a poor outcome. Kinase-activating alterations were identified in 91% of patients with Ph-like ALL; rearrangements involving ABL1, ABL2, CRLF2, CSF1R, EPOR, JAK2, NTRK3, PDGFRB, PTK2B, TSLP, or TYK2 and sequence mutations involving FLT3, IL7R, or SH2B3 were most common. Expression of ABL1, ABL2, CSF1R, JAK2, and PDGFRB fusions resulted in cytokine-independent proliferation and activation of phosphorylated STAT5. Cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R, and PDGFRB fusions were sensitive in vitro to dasatinib, EPOR and JAK2 rearrangements were sensitive to ruxolitinib, and the ETV6-NTRK3 fusion was sensitive to crizotinib.
CONCLUSIONS: Ph-like ALL was found to be characterized by a range of genomic alterations that activate a limited number of signaling pathways, all of which may be amenable to inhibition with approved tyrosine kinase inhibitors. Trials identifying Ph-like ALL are needed to assess whether adding tyrosine kinase inhibitors to current therapy will improve the survival of patients with this type of leukemia. (Funded by the American Lebanese Syrian Associated Charities and others.).

Related: Signal Transduction

Dunna NR, Vuree S, Anuradha C, et al.
NRAS mutations in de novo acute leukemia: prevalence and clinical significance.
Indian J Biochem Biophys. 2014; 51(3):207-10 [PubMed] Related Publications
The activating mutations of the Ras gene or other abnormalities in Ras signaling pathway lead to uncontrolled growth factor-independent proliferation of hematopoietic progenitors. Oncogenic mutations in NRAS gene have been observed with variable prevalence in hematopoietic malignancies. In the present study, NRAS mutations were detected using bidirectional sequencing in 264 acute leukemia cases--129 acute lymphocytic leukemia (ALL) and 135 acute myeloid leukemia (AML) and 245 age- and gender-matched controls. Missense mutation was observed only in the 12th codon of NRAS gene in 4.7% of AML and 3.16% of ALL cases. The presence of NRAS mutation did not significantly influence blast % and lactate dehydrogenase (LDH) levels in AML patients. When the data were analyzed with respect to clinical variables, the total leukocyte count was elevated for mutation positive group, compared to negative group. In AML patients with NRAS mutations, 60% failed to achieve complete remission (CR), as compared to 34.8% in mutation negative group. These results indicated that NRAS mutations might confer poor drug response. In AML, disease free survival (DFS) in NRAS mutation positive group was lesser, compared to mutation negative group (9.5 months vs. 11.68 months). In ALL patients, DFS of NRAS mutation positive group was lesser than mutation negative group (9.2 months vs. 27.5 months). The CR rate was also lower for mutation-positive patients group, compared to mutation-negative group. In conclusion, these results suggested that presence of NRAS mutation at 12th codon was associated with poor response and poorer DFS in both ALL and AML.

Related: Acute Myeloid Leukemia (AML) Acute Lymphocytic Leukemia (ALL) NRAS gene

Barbouch S, Gaied H, Abdelghani KB, et al.
Chronic graft versus host disease and nephrotic syndrome.
Saudi J Kidney Dis Transpl. 2014; 25(5):1062-4 [PubMed] Related Publications
Disturbed kidney function is a common complication after bone marrow transplantation. Recently, attention has been given to immune-mediated glomerular damage related to graft versus host disease (GVHD). We describe a 19-year-old woman who developed membranous glomerulonephritis after bone marrow transplantation (BMT). Six months later, she developed soft palate, skin and liver lesions considered to be chronic GVHD. Fifteen months after undergoing BMT, this patient presented with nephrotic syndrome. A renal biopsy showed membranous glomerulonephritis associated with a focal segmental glomerulosclerosis. She was started on corticosteroid treatment with good outcome.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Bosutinib. Chronic myeloid leukaemia in treatment failure: major toxicity.
Prescrire Int. 2014; 23(151):177 [PubMed] Related Publications
Retrospective analysis of data on 52 patients in whom other tyrosine kinase inhibitors had failed or were poorly tolerated. Beware of frequent and often serious adverse effects with bosutinib, including diarrhoea and hepatotoxicity.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Polednak AP
Recent improvement in completeness of incidence data on acute myeloid leukemia in US cancer registries.
J Registry Manag. 2014; 41(2):77-84 [PubMed] Related Publications
A limitation of data prior to 2010 on incidence of leukemia in US population-based cancer registries is that acute myeloid leukemia (AML) diagnosed as progression (transformation) from a previously diagnosed myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN, other than polycythemia vera), or chronic myeloid leukemia (CML) was not reportable. Data were used from a research database for the 18 cancer registries of the Surveillance, Epidemiology and End Results (SEER) Program, and from all registries in the US Cancer Statistics (USCS) database. Analyses compared the age-standardized incidence rate (ASIR) per 100,000 for AML before (ie, 2000-2009) vs after (ie, 2010) the new reportability rules for AML. The ASIR for all ages combined fluctuated until increasing from 3.60 (95 percent CI, 3.47-3.73; N = 3,068) in 2009 to 3.89 (95 percent CI, 3.76-4.03; N = 3,355) in 2010 in SEER, and from 3.64 (95 percent CI, 3.58-3.71; N = 11,488) in 2009 to 3.89 (95 percent CI, 3.82-3.96; N = 12,351) in 2010 in USCS. The increase from 2009 to 2010 was limited to ages 60+ years (from 13.87 to 15.59 in SEER and from 14.13 to 15.34 in USCS). The SEER research database allowed analysis by the number of cancers per person, which showed that the increase in AML cases and rates for age 60+ years from 2009 to 2010 was due to an increase in cases with a previous cancer(s) largely representing newly-reportable post-MDS, post-MPN and post-CML AML cases. Continued surveillance is needed to address the eventual impact of delayed reporting of diagnoses in 2010 on estimates and projections of AML incidence in the US population.

Related: Chronic Myeloid Leukemia (CML) CML - Molecular Biology Acute Myeloid Leukemia (AML) Cancer Prevention and Risk Reduction

Flatley E, Chen AI, Zhao X, et al.
Aberrations of MYC are a common event in B-cell prolymphocytic leukemia.
Am J Clin Pathol. 2014; 142(3):347-54 [PubMed] Related Publications
OBJECTIVES: B-cell prolymphocytic leukemia (B-PLL) remains a controversial entity, and its molecular pathogenesis is largely unknown. Patients are older, typically having marked lymphocytosis and splenomegaly in the absence of lymphadenopathy. It is defined as a mature B-cell leukemia with more than 55% circulating prolymphocytes. Leukemic mantle cell lymphoma and chronic lymphocytic leukemia in prolymphocytic transformation must be excluded.
METHODS: Case archives were retrospectively reviewed for B-PLL in patients without a previous diagnosis of chronic lymphocytic leukemia or other B-cell neoplasm.
RESULTS: We identified six cases of B-PLL with available cytogenetic data, five of which showed evidence of aberrations in MYC. Three cases showed additional signals for the MYC gene by fluorescence in situ hybridization (FISH), and two cases demonstrated t(8;14)MYC/IGH by karyotyping or FISH. High levels of MYC protein expression were detected in all cases tested with MYC aberrations.
CONCLUSIONS: These results suggest that deregulation of MYC plays an important role in the pathogenesis of B-PLL and expands the spectrum of B-cell neoplasms associated with aberrations of MYC.

Related: FISH

Ishikawa M, Nakayama K, Rahman MT, et al.
Therapy-related myelodysplastic syndrome and acute myeloid leukemia following chemotherapy (paclitaxel and carboplatin) and radiation therapy in ovarian cancer: a case report.
Eur J Gynaecol Oncol. 2014; 35(4):443-8 [PubMed] Related Publications
In recent years, the incidence of therapy-related myelodysplastic syndrome (t-MDS) and therapy-related acute myeloid leukemia (t-AML) that occur during chemotherapy for ovarian cancer has increased. While alkylating agents and topoisomerase II inhibitors are particularly mutagenic and have strong leukemogenic potential, paclitaxel and combination chemotherapy/radiation therapy also appear to induce t-MDS. The present authors report a case of t-MDS that developed during chemotherapy and radiation therapy for ovarian cancer. The patient was a 75-year-old woman who received six courses of cyclophosphamide/doxorubicin/cisplatin (CAP) therapy after initial surgery for Stage IIIc grade ovarian cancer in 1995. Beginning in February 2005, the patient experienced multiple recurrences due to sternal metastasis. Chemotherapy, including paclitaxel and carboplatin (TC), was administered intermittently and was combined with radiation therapy to a sternal metastatic lesion. Pancytopenia was observed in December 2008, and she was diagnosed with t-MDS (WHO subtype, refractory cytopenias with multilineage dysplasia [RCMD]): the time from first chemotherapy to t-MDS onset was 106 months. Without evidence of blast crisis, the recurrent lesions continued to grow and caused multiple cerebral infarctions, from which she eventually died. The cumulative doses of paclitaxel and carboplatin administered to this patient were 1,968 mg and 6,480 mg, respectively.

Related: Carboplatin Acute Myeloid Leukemia (AML) Ovarian Cancer Paclitaxel

Cao K, Shilatifard A
Inhibit globally, act locally: CDK7 inhibitors in cancer therapy.
Cancer Cell. 2014; 26(2):158-9 [PubMed] Related Publications
Cyclin-dependent kinases (CDKs) are involved in temporal control of the cell cycle and transcription and play central roles in cancer development and metastasis. Recently, Kwiatkowski and colleagues identified a novel CDK7-specific inhibitor, THZ1, that hinders proliferation in cancer cell lines and dampens global transcription in T cell leukemia.

Hall G, McGuire E
Milk supply related to childhood leukaemia treatment.
Breastfeed Rev. 2014; 22(2):29-31 [PubMed] Related Publications
This literature review and case study answers the question: 'Do the late effects of childhood cranial radiation therapy include impacts on breastfeeding?' PubMed was searched for papers using the terms lactation and cranial radiotherapy or childhood cranial radiotherapy. The case study was written from one author's experience of helping a mother with a history of childhood cranial radiation therapy. The few available studies report a high rate of lactation failure in women who were treated with cranial radiation therapy for childhood cancer, but the exceptions indicate that lactation failure is not inevitable in this group of mothers. Breastfeeding may ameliorate some of the adverse effects of cranial radiation therapy. Health professionals caring for mothers with a history of cranial radiation therapy must balance encouraging women to breastfeed with preparing them for the possibility that they may be unable to do so.

Related: Acute Lymphocytic Leukemia (ALL)

Beach JA, Nary LJ, Hovanessian R, Medh RD
Correlation of glucocorticoid-mediated E4BP4 upregulation with altered expression of pro- and anti-apoptotic genes in CEM human lymphoblastic leukemia cells.
Biochem Biophys Res Commun. 2014; 451(3):382-8 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
In Caenorhabditiselegans, motorneuron apoptosis is regulated via a ces-2-ces-1-egl-1 pathway. We tested whether human CEM lymphoblastic leukemia cells undergo apoptosis via an analogous pathway. We have previously shown that E4BP4, a ces-2 ortholog, mediates glucocorticoid (GC)-dependent upregulation of BIM, an egl-1 ortholog, in GC-sensitive CEM C7-14 cells and in CEM C1-15mE#3 cells, which are sensitized to GCs by ectopic expression of E4BP4. In the present study, we demonstrate that the human ces-1 orthologs, SLUG and SNAIL, are not significantly repressed in correlation with E4BP4 expression. Expression of E4BP4 homologs, the PAR family genes, especially HLF, encoding a known anti-apoptotic factor, was inverse to that of E4BP4 and BIM. Expression of pro- and anti-apoptotic genes in CEM cells was analyzed via an apoptosis PCR Array. We identified BIRC3 and BIM as genes whose expression paralleled that of E4BP4, while FASLG, TRAF4, BCL2A1, BCL2L1, BCL2L2 and CD40LG as genes whose expression was opposite to that of E4BP4.

Related: Apoptosis Acute Lymphocytic Leukemia (ALL)

D'Souza P, Walker G
Spotlight on chronic lymphocytic leukemia: a Pharma Matters report.
Drugs Today (Barc). 2014; 50(7):485-501 [PubMed] Related Publications
A paradigm shift in the treatment of chronic lymphocytic leukemia (CLL) has taken place over the past decade, as therapies have progressed from providing palliative relief to inducing complete remission, eradicating minimal disease and improving survival. The development of Rituxan® (rituximab) and its use in immunochemotherapy regimens has transformed the treatment of CLL and is the current gold standard in physically fit individuals aged < 65 years. Despite this therapeutic development, Rituxan-based immunochemotherapy is limited in the two CLL groups that form the majority of CLL cases-the elderly and patients with comorbidities and high risk factors. Moreover, within 2 years of first- and second-line therapy, around 25% and 50% of patients relapse, respectively, and patients who experience remission for several years exhibit poor responses to subsequent therapies. Therefore, there still remains a significant unmet need in CLL. The rapid development of small-molecule agents targeting the B-cell receptor signaling pathway has been stimulated both by the association of this pathway with the initiation and progression of CLL as well as the high response rates and durable remissions reported in early-stage trials. Imbruvica (ibrutinib), an oral first-in-class Bruton's tyrosine kinase inhibitor, recently entered the market following accelerated approval in the relapsed/refractory setting, but long-term survival data are currently immature. New therapies face several significant challenges: to provide even greater response rates, particularly in the elderly and in patients with comorbidities and high risk factors, and to overcome resistance to current treatments. Currently, the only curative treatment for CLL, allogeneic hematopoietic stem cell transplantation, is not an option for the majority of CLL patients. The ultimate question is whether small-molecule therapeutics can achieve a cure for CLL. It is hoped that developments in identifying the cytogenetic and molecular changes associated with the prognosis and pathogenesis of CLL will enable the rapid development of next-generation targeted therapies.

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

Korf K, Wodrich H, Haschke A, et al.
The PML domain of PML-RARα blocks senescence to promote leukemia.
Proc Natl Acad Sci U S A. 2014; 111(33):12133-8 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
In most acute promyelocytic leukemia (APL) cases, translocons produce a promyelocytic leukemia protein-retinoic acid receptor α (PML-RARα) fusion gene. Although expression of the human PML fusion in mice promotes leukemia, its efficiency is rather low. Unexpectedly, we find that simply replacing the human PML fusion with its mouse counterpart results in a murine PML-RARα (mPR) hybrid protein that is transformed into a significantly more leukemogenic oncoprotein. Using this more potent isoform, we show that mPR promotes immortalization by preventing cellular senescence, impeding up-regulation of both the p21 and p19(ARF) cell-cycle regulators. This induction coincides with a loss of the cancer-associated ATRX/Daxx-histone H3.3 predisposition complex and suggests inhibition of senescence as a targetable mechanism in APL therapy.

El Rassi F, Ward KC, Flowers CR, et al.
Incidence and geographic distribution of adult acute leukemia in the state of Georgia.
South Med J. 2014; 107(8):497-500 [PubMed] Related Publications
OBJECTIVE: We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referrals from northern Georgia to a tertiary care center located in Atlanta.
METHODS: Cases reported to the Georgia Comprehensive Cancer Registry and the national Surveillance Epidemiology and End Results cancer registry between 1999 and 2008 were analyzed. Age-adjusted incidence rates were calculated for all of the counties and public health regions and were compared with national rates calculated using Surveillance Epidemiology and End Results 17 data. Cases of adult acute myeloid leukemia served as controls.
RESULTS: Age-adjusted incidence rates of adult ALL (0.8/100,000) and acute myeloid leukemia (4.6/100,000) were comparable to the national rates (0.9 and 5.2, respectively). The age-adjusted incidence rate of ALL in northern Georgia was 1.1 (95% confidence interval 0.8-1.5) and was not affected by race.
CONCLUSIONS: The observed increase in cases of ALL at our tertiary center results from a referral pattern rather than heterogeneous distribution of adult ALL across Georgia.

Cupedo T
Innate protection from graft-versus-host disease.
Blood. 2014; 124(5):673-5 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
n this issue of Blood, Hazenberg and Spits provide a detailed overview of human innate lymphoid cell (ILC) subsets and their development and distribution throughout the human body, discussing these cells in the context of human disease. In the same issue, Munneke et al for the first time link ILCs to human hematopoietic malignancies by identifying a clear correlation between the presence of activated ILCs after induction chemotherapy and the absence of acute graft-versus-host disease (GVHD) development following subsequent hematopoietic stem cell transplantation (HSCT).

Zirlik K
MDSCs: the final frontier of the microenvironment in CLL?
Blood. 2014; 124(5):666-8 [PubMed] Article available free on PMC after 29/08/2015 Related Publications
In this issue of Blood, Jitschin et al identify increased numbers of myeloid-derived suppressor cells (MDSCs) in untreated patients with chronic lymphocytic leukemia (CLL) suppressing T cells and inducing regulatory T cells (T(regs)), resulting in impaired immune responses.

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

Bailón E, Ugarte-Berzal E, Amigo-Jiménez I, et al.
Overexpression of progelatinase B/proMMP-9 affects migration regulatory pathways and impairs chronic lymphocytic leukemia cell homing to bone marrow and spleen.
J Leukoc Biol. 2014; 96(2):185-99 [PubMed] Related Publications
This study addresses the role of (pro)MMP-9 overexpression in CLL cell migration. We have used primary CLL cells and CLL-derived MEC-1 cells transfected with empty (mock cells) or proMMP-9-encoding (MMP-9 cells) lentiviral vectors. The constitutive (pro)MMP-9 expression in mock cells and primary CLL cells was similar, whereas in MMP-9 cells, expression resembled that of CLL cells incubated with proMMP-9. In xenograft models, in NOD/SCID mice, MMP-9-MEC-1 transfectants showed significantly reduced homing to bone marrow and spleen compared with mock cells. Likewise, incubation of primary CLL cells with proMMP-9, before injection into mice, inhibited their homing to these organs. This inhibition was specific, dose-dependent, and observed in all CLL tested, independently of prognostic markers or disease stage. Additionally, the MMP-9 catalytic activity was only partially involved, as the inactive mutant proMMP-9MutE had a partial effect. MMP-9 cells also showed impaired migration in vitro, which was reverted by reducing (pro)MMP-9 expression with siRNAs. CLL migration thus requires optimal (pro)MMP-9 expression levels, below or above which migration is hampered. Biochemical analysis of the (pro)MMP-9 effect indicated that MMP-9 cells or primary CLL cells incubated with proMMP-9 had reduced activation of migration regulatory molecules, including RhoAGTPase, Akt, ERK, and FAK. In contrast, p190RhoGAP (RhoA inhibitor) and PTEN (Akt/ERK/FAK inhibitor) were up-regulated in MMP-9 cells. Reduction of (pro)MMP-9 expression by siRNAs restored RhoA activity and diminished PTEN levels. Our results reveal a novel function for (pro)MMP-9 in modulating signaling pathways leading to CLL cell arrest. Therefore, local high (pro)MMP-9 expression may contribute to malignant cell retention in lymphoid organs and disease progression.

Related: Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology MMP9: matrix metallopeptidase 9 AKT1 Signal Transduction

Wolfe AL, Singh K, Zhong Y, et al.
RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.
Nature. 2014; 513(7516):65-70 [PubMed] Related Publications
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

Zhao XY, Chang YJ, Xu LP, et al.
HLA and KIR genotyping correlates with relapse after T-cell-replete haploidentical transplantation in chronic myeloid leukaemia patients.
Br J Cancer. 2014; 111(6):1080-8 [PubMed] Related Publications
BACKGROUND: Conflicting results have been reported regarding the predicative roles of alloreactive natural killer (NK) cells on the outcomes of transplantation in leukaemia patients.
METHODS: We prospectively analysed the human leukocyte antigen (HLA) typing of donor-recipient pairs and the KIR typing of the donors in 97 CML patients to address the predictive roles of NK cells in relapse undergoing T-cell-replete haploidentical transplantation.
RESULTS: Patients with class I ligands for the donor-inhibitory KIR gene exhibited decreased molecular and haematologic relapse rates (P=0.003 and P=0.015, respectively). There was a significantly reduced risk of molecular and haematologic relapse in patients with HLA-C1C2 or C2C2 who accepted donors with KIR2DS1 or in patients with HLA-Bw4 who accepted donors with KIR3DS1 ('recipient with relevant KIR ligand for donor-activating KIR', n=25), compared with the remaining transplants (n=72, P=0.009 and P=0.009, respectively). In addition, the presence of class I ligand in the recipients of donor-activating KIR contributed to a decreased relapse rate in patients lacking class I ligand in the recipient of donor-inhibitory KIR (P=0.04 and P=0.03, respectively).
CONCLUSIONS: This study suggests that the presence of class I ligands for the donor-activating or donor-inhibitory KIR gene in the recipient might confer some protection against leukaemic relapse in T-cell-replete haploidentical transplantation.

Related: HLA-B Chronic Myeloid Leukemia (CML) CML - Molecular Biology

Shaver AC, Ma L, Vnencak-Jones C, et al.
Transformation of small B-cell lymphoma into large cell CD30⁺, CD4⁺, Epstein-Barr virus-negative lymphoma.
Arch Pathol Lab Med. 2014; 138(8):1101-5 [PubMed] Related Publications
We report here 2 separate cases in which patients with known low-grade B-cell lymphomas presented with transformed lesions that were CD30⁺, CD4⁺, Epstein-Barr virus negative, and negative or focally weak for a wide range of B-cell, T-cell, and histiocytic/dendritic cell markers. In each case the transformed lymphoma possessed an identical pattern of immunoglobulin heavy chain and/or BCL2 rearrangement to the corresponding original low-grade B-cell lymphoma, confirming their identity as transformed B-cell lymphoma. A review of the relevant literature reveals that, to our knowledge, no transformed B-cell lymphomas with this immunophenotype have been previously reported, which creates the opportunity for potential errors of diagnosis. These cases highlight the importance of correlation with the patient's history and with molecular genetic results in rendering an accurate diagnosis.

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

Rose-Inman H, Kuehl D
Acute leukemia.
Emerg Med Clin North Am. 2014; 32(3):579-96 [PubMed] Related Publications
Although great progress has been made in the understanding and treatment of acute leukemia, this disease has not been conquered. For emergency providers (EPs), the presentation of these patients to an emergency department presents a host of challenges. A patient may present with a new diagnosis of leukemia or with complications of the disease process or associated chemotherapy. It is incumbent on EPs to be familiar with the manifestations of leukemia in its various stages and maintain some suspicion for this diagnosis, given the nebulous and insidious manner in which leukemia can present.

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

Pallasch CP, Hallek M
Incorporating targeted agents into future therapy of chronic lymphocytic leukemia.
Semin Hematol. 2014; 51(3):235-48 [PubMed] Related Publications
Treatment of chronic lymphocytic leukemia (CLL) is currently undergoing profound changes. Several monoclonal antibodies (ofatumumab and obinutuzumab), and the first agent targeting essential signaling cascades in CLL (ibrutinib) have recently been approved. Inhibiting the B-cell receptor pathway seems of particular importance in effective targeted therapies of CLL. Here, inhibition of Bruton's tyrosine kinase and phosphatidylinositol 3-kinase delta currently offer the most promising targeted approaches. The clinical course of CLL presents with an impressive heterogeneity. During recent years, the combined use of clinical, biologic, and genetic parameters has allowed characterization of at least three categories of patients(1): (1) patients with a very mild onset and course; (2) patients with an intermediate prognosis; and (3) patients with an aggressive course of high-risk leukemia. With this background, it becomes increasingly challenging to select the right treatment strategy for each patient. In the present article, we summarize the current therapeutic tools and their combination partner drugs. Moreover, we offer a perspective on how to integrate the novel targeted agents for CLL therapy into sequential treatment approaches.

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

Riches JC, Gribben JG
Immunomodulation and immune reconstitution in chronic lymphocytic leukemia.
Semin Hematol. 2014; 51(3):228-34 [PubMed] Related Publications
Over the past decade, there have been significant advances in our understanding of the pathogenesis of chronic lymphocytic leukemia (CLL), which has been accompanied by an explosion in treatment options. Although the combination of fludarabine, cyclophosphamide, and rituximab is the current frontline treatment of choice for fit patients, targeted therapies such ibrutinib, idelalisib, and ABT-199 are showing great promise in clinical trials. However, none of these drugs seems curative, and allogeneic hematopoietic stem cell transplantation remains the only strategy that produces durable clinical remissions in otherwise poor-risk disease. Immune reconstitution remains an enticing prospect in CLL, as malignant B cells should be particularly susceptible to a T cell-mediated attack. It has recently been demonstrated that the T-cell defect in CLL can be effectively overcome by both lenalidomide treatment and by adoptive transfer of chimeric antigen receptor T cells. A variety of other immunotherapies are in development, including CLL vaccines, CD40 ligand therapies, and monoclonal antibody immune checkpoint blockade. This review explores the nature of the immune defect in CLL and summarizes the recent developments in the immunotherapeutic field.

Related: Monoclonal Antibodies Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology Thalidomide Lenalidomide

Anderson MA, Huang D, Roberts A
Targeting BCL2 for the treatment of lymphoid malignancies.
Semin Hematol. 2014; 51(3):219-27 [PubMed] Related Publications
The failure of apoptosis (programmed cell death) underpins the development of many tumors and often renders them resistant to cytotoxic therapies. In hematologic malignancies, this impairment of apoptosis is often caused by overexpression of the pro-survival protein BCL2. Because abnormally high levels of BCL2 sustain these tumors, there has been much interest in targeting BCL2 as a novel approach to treating various hematologic malignancies. One such approach is the development of BH3 mimetic compounds, small molecules that mimic the action of the BH3-only proteins, natural antagonists of BCL2 and its pro-survival relatives. These compounds act by restoring the ability of a cell to undergo apoptotic cell death. Some of them have shown very encouraging results in early-phase clinical trials that are currently underway, particularly in patients with chronic lymphocytic leukemia and some non-Hodgkin lymphomas, diseases marked by BCL2 overexpression. In this review, we discuss the rationale behind targeting BCL2, highlight the recent findings from clinical trials, and pinpoint the next steps in the clinical development of this interesting and promising class of targeted agents, particularly for the treatment of lymphoid malignancies.

Related: Haematological Malignancies & Realted Disorders Chronic Lymphocytic Leukemia (CLL) CLL - Molecular Biology

Chen SS, Chiorazzi N
Murine genetically engineered and human xenograft models of chronic lymphocytic leukemia.
Semin Hematol. 2014; 51(3):188-205 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a genetically complex disease, with multiple factors having an impact on onset, progression, and response to therapy. Genetic differences/abnormalities have been found in hematopoietic stem cells from patients, as well as in B lymphocytes of individuals with monoclonal B-cell lymphocytosis who may develop the disease. Furthermore, after the onset of CLL, additional genetic alterations occur over time, often causing disease worsening and altering patient outcomes. Therefore, being able to genetically engineer mouse models that mimic CLL or at least certain aspects of the disease will help us understand disease mechanisms and improve treatments. This notwithstanding, because neither the genetic aberrations responsible for leukemogenesis and progression nor the promoting factors that support these are likely identical in character or influences for all patients, genetically engineered mouse models will only completely mimic CLL when all of these factors are precisely defined. In addition, multiple genetically engineered models may be required because of the heterogeneity in susceptibility genes among patients that can have an effect on genetic and environmental characteristics influencing disease development and outcome. For these reasons, we review the major murine genetically engineered and human xenograft models in use at the present time, aiming to report the advantages and disadvantages of each.

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

Gruber M, Wu CJ
Evolving understanding of the CLL genome.
Semin Hematol. 2014; 51(3):177-87 [PubMed] Article available free on PMC after 01/07/2015 Related Publications
Over the past few years, massively parallel sequencing technologies have revealed with high resolution the tremendous genetic and epigenetic heterogeneity in chronic lymphocytic leukemia (CLL). We have learned how the molecular architecture differs not only between affected individuals but also within samples and over time. These insights have catalyzed our understanding of the pathobiology of CLL and point to critical signaling pathways in the development and progression of the disease. Several key driver alterations have been identified, which serve to refine prognostic schemata but also to inspire the development of new therapeutic strategies. Ongoing advances in technology promise to further elucidate the molecular basis of CLL, and this knowledge is anticipated to aid us in understanding and addressing the clinical challenge presented by the vast variability in the clinical course of patients with CLL.

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

Dal Bo M, Tissino E, Benedetti D, et al.
Microenvironmental interactions in chronic lymphocytic leukemia: the master role of CD49d.
Semin Hematol. 2014; 51(3):168-76 [PubMed] Related Publications
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous disease characterized by the accumulation/expansion of a clonal population of neoplastic cells with the morphologic appearance of small mature B lymphocytes in blood, bone marrow, and lymphoid organs. A combination of genetic lesions is primarily responsible for the first step(s) of neoplastic transformation, along with microenvironmental signals, which concurrently operate by enhancing proliferation and/or inhibiting apoptosis. In this context, CD49d is known to play a pivotal role in mediating both cell-cell and cell-matrix interactions in CLL-involved tissues, eventually delivering pro-survival signals and protecting CLL cells from drug-induced damages. In the present review, we address, in detail, CD49d activities in the CLL microenvironment, CD49d functional and physical interactions with other microenvironmental receptors (including CD38 and B-cell receptor), and the relationship of CD49d expression with specific cytogenetic features in CLL.

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

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