Posts Tagged ‘CLL’

Infinity and AbbVie partner to develop and commercialise Duvelisib for cancer… for the treatment of chronic lymphocytic leukemia.

Duvelisib is a dual phosphoinositide-3-kinase (PI3K) delta and PI3K gamma inhibitor.  The delta and gamma isozymes are selectively expressed in leukocytes.    This article (at Dr. Melvin Crasto’s blog discusses the synthesis of Duvelisib and mentions additional clinical trials underway including a phase II trial for the treatment of patients with mild asthma undergoing allergen challenge, for the treatment of rheumatoid arthritis and for the treatment of refractory indolent non-Hodgkin’s lymphoma. Phase I clinical trials for the treatment of advanced hematological malignancies (including T-cell lymphoma and mantle cell lymphoma).  The drug was originally developed at Takeda subsidiary Intellikine.


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Larry H. Benstein, MD, FCAP, Gurator and writer on mitochondrial function, respiration, and associated disorders

This is a condensed account of very recent published work on respiration and disturbed mitochondrail function.  We know that their is an equilibrium between respiration and autophagy in eukaryotic cells.  The Krebs Cycle produces 32 ATPs in oxidative phosphorylation, which is far more efficient than glycolysis.  There is also a different contribution of mitochondrial metabolism, in the balance, between tissues that are synthetic and those that are catabolic.  This is a subject long understood, essential for cellular energetics, and not adequately explored.


Gain-of-Function Mutant p53 Promotes Cell Growth and Cancer Cell Metabolism via Inhibition of AMPK Activation.

Zhou G1Wang J2Zhao M2Xie TX2Tanaka N2, et al.
Mol Cell. 
2014 Jun 19;54(6):960-974.   doi: 10.1016/j.molcel.2014.04.024. 

Many mutant p53 proteins (mutp53s) exert oncogenic gain-of-function (GOF) properties, but the mechanisms mediating these functions remain poorly defined.

We show here that GOF mutp53s inhibit AMP-activated protein kinase (AMPK) signaling in head and neck cancer cells.

Conversely, downregulation of GOF mutp53s enhances AMPK activation under energy stress, decreasing the activity of the anabolic factors acetyl-CoA carboxylase and ribosomal protein S6 and inhibiting aerobic glycolytic potential and invasive cell growth.

Under conditions of energy stress, GOF mutp53s, but not wild-type p53, preferentially bind to the AMPKα subunit and inhibit AMPK activation.

Given the importance of AMPK as an energy sensor and tumor suppressor that inhibits anabolic metabolism, our findings reveal that direct inhibition of AMPK activation is an important mechanism through which mutp53s can gain oncogenic function. PMID:24857548

Investigating and Targeting Chronic Lymphocytic Leukemia Metabolism with the HIV Protease Inhibitor Ritonavir and Metformin.

Adekola KUAydemir SDMa SZhou ZRosen STShanmugam M.
Leuk Lymphoma. 2014 May 14:1-23.

Chronic Lymphocytic Leukemia (CLL) remains fatal due to the development of resistance to existing therapies. Targeting abnormal glucose metabolism sensitizes various cancer cells to chemotherapy and/or elicits toxicity.

Examination of glucose dependency in CLL demonstrated variable sensitivity to glucose deprivation. Further evaluation of metabolic dependencies of CLL cells resistant to glucose deprivation revealed increased engagement of fatty acid oxidation upon glucose withdrawal.

Investigation of glucose transporter expression in CLL reveals up-regulation of glucose transporter GLUT4. Treatment of CLL cells with HIV protease inhibitor ritonavir, that inhibits GLUT4, elicits toxicity similar to that elicited upon glucose-deprivation.

CLL cells resistant to ritonavir are sensitized by co-treatment with metformin, potentially targeting compensatory mitochondrial complex 1 activity. Ritonavir and metformin have been administered in humans for treatment of diabetes in HIV patients, demonstrating the tolerance of this combination in humans. Our studies strongly substantiate further investigation of FDA approved ritonavir and metformin for CLL.

KEYWORDS:  Basic Biology; Chemotherapeutic approaches; Lymphoid Leukemia; Signal transduction             PMID: 24828872

Utilizing hydrogen sulfide as a novel anti-cancer agent by targeting cancer glycolysis and pH imbalance.

Lee ZW1Teo XYTay EYTan CHHagen TMoore PKDeng LW.
Br J Pharmacol. 2014 May 15.    doi: 10.1111/bph.12773

Many disparate studies have reported the ambiguous role of hydrogen sulfide (H2 S) in cell survival. The present study investigated the effect of H2 S on viability of cancer and non-cancer cells.

Cancer and non-cancer cells were exposed to H2 S (using sodium hydrosulfide, NaHS and GYY4137) and cell viability was examined by crystal violet assay. We then examined cancer cellular glycolysis process by in vitro enzymatic assays and pH regulator activity. Lastly, intracellular pH (pHi) was determined by ratiometric pHi measurement using BCECF staining.

Continuous, but not single, exposure to H2 S decreased cell survival more effectively in cancer cells, as compared to non-cancer cells. Slow H2 S-releasing donor, GYY4137, significantly increased glycolysis leading to overproduction of lactate. H2 S also decreased anion exchanger and sodium/proton exchanger activity. The combination of increased metabolic acid production and defective pH regulation resulted in an uncontrolled intracellular acidification leading to cancer cell death. In contrast, no significant intracellular acidification or cell death was observed in non-cancer cells.

Low and continuous exposure to H2 S targets metabolic processes and pH homeostasis in cancer cells, potentially serving as a novel and selective anti-cancer strategy.

KEYWORDS:  cancer cell death; cancer glucose metabolism; hydrogen sulfide; pH homeostasis          PMID: 24827113

Agonism of the 5-Hydroxytryptamine 1F Receptor Promotes Mitochondrial Biogenesis and Recovery from Acute Kidney Injury

Garrett SMWhitaker RMBeeson CC, and Schnellmann RG

Center for Cell Death, Injury, and Regeneration, Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina (S.M.G., R.M.W., C.C.B., R.G.S.); and Ralph H. Johnson Veterans Affairs Medical Center, Charleston, South Carolina (R.G.S.)
Address correspondence to: Dr. Rick G. Schnellmann, Department of Drug Discovery and Biomedical Sciences, MUSC, Charleston, SC 29425.

Many acute and chronic conditions, such as acute kidney injury, chronic kidney disease, heart failure, and liver disease, involve mitochondrial dysfunction. Although we have provided evidence that drug-induced stimulation of mitochondrial biogenesis (MB) accelerates mitochondrial and cellular repair, leading to recovery of organ function, only a limited number of chemicals have been identified that induce MB.

The goal of this study was to assess the role of the 5-hydroxytryptamine 1F (5-HT1F) receptor in MB. Immunoblot and quantitative polymerase chain reaction analyses revealed 5-HT1F receptor expression in renal proximal tubule cells (RPTC). A MB screening assay demonstrated that two selective 5-HT1F receptor agonists,

  1. LY334370 (4-fluoro-N-[3-(1-methyl-4-piperidinyl)-1H-indol-5-yl]benzamide) and
  2. LY344864 (N-[(3R)-3-(dimethylamino)-2,3,4,9-tetrahydro-1H-carbazol-6-yl]-4-fluorobenzamide; 1–100 nM)

increased carbonylcyanide-p-trifluoromethoxyphenylhydrazone–uncoupled oxygen consumption in RPTC, and

  • validation studies confirmed both agonists increased mitochondrial proteins  in vitro.
    [e.g., ATP synthase β, cytochrome c oxidase 1 (Cox1), and NADH dehydrogenase (ubiquinone) 1β subcomplex subunit 8 (NDUFB8)]

Small interfering RNA knockdown of the 5-HT1F receptor

  • blocked agonist-induced MB.

Furthermore, LY344864 increased

  • peroxisome proliferator–activated receptor (PPAR) coactivator 1-α, Cox1, and
  • NDUFB8 transcript levels and
  • mitochondrial DNA (mtDNA) copy number

in murine renal cortex, heart, and liver.

Finally, LY344864 accelerated recovery of renal function, as indicated by

  • decreased blood urea nitrogen and kidney injury molecule 1 and
  • increased mtDNA copy number

following ischemia/reperfusion-induced acute kidney injury (AKI).

In summary, these studies reveal that

  • the 5-HT1F receptor is linked to MB, 5-HT1F receptor agonism promotes MB in vitro and in vivo, and

5-HT1F receptor agonism promotes recovery from AKI injury.

Induction of MB through 5-HT1F receptor agonism represents a new target and approach to treat mitochondrial organ dysfunction.


  • Portions of this work have been presented previously: Garrett SM, Wills LP, and Schnellmann RG (2012) Serotonin (5-HT) 1F receptor agonism as a potential treatment for acceleration of recovery from acute kidney injury.American Society of Nephrology Annual Meeting; 2012 Nov 1–4; San Diego, CA.

Ca2+ regulation of mitochondrial function in neurons.

Rueda CB1Llorente-Folch I1Amigo I1Contreras L1González-Sánchez P1Martínez-Valero P1Juaristi I1Pardo B1Del Arco A2Satrústegui J3

Biochim Biophys Acta. 2014 May 10. pii: S0005-2728(14)00126-1.
doi: 10.1016/j.bbabio.2014.04.010.

Calcium is thought to regulate respiration but it is unclear whether this is dependent on the increase in ATP demand caused by any Ca2+ signal or to Ca2+ itself.

[Na+]i, [Ca2+]i and [ATP]i dynamics in intact neurons exposed to different workloads in the absence and presence of Ca2+ clearly showed that

  • Ca2+-stimulation of coupled respiration is required to maintain [ATP]i levels.

Ca2+ may regulate respiration by

  1. activating metabolite transport in mitochondria from outer face of the inner mitochondrial membrane, or
  2. after Ca2+ entry in mitochondria through the calcium uniporter (MCU).

Two Ca2+-regulated mitochondrial metabolite transporters are expressed in neurons,

  1. the aspartate-glutamate exchanger ARALAR/AGC1/Slc25a12, a component of the malate-aspartate shuttle, with a Kd for Ca2+ activation of 300nM, and
  2. the ATP-Mg/Pi exchanger SCaMC-3/Slc25a23, with S0.5 for Ca2+ of 300nM and 3.4μM, respectively.

The lack of SCaMC-3 results in a smaller Ca2+-dependent stimulation of respiration only at high workloads, as caused by veratridine, whereas

  • the lack of ARALAR reduced by 46% basal OCR in intact neurons using glucose as energy source and the Ca2+-dependent responses to all workloads (veratridine, K+-depolarization, carbachol).

The lack of ARALAR caused a reduction of about 65-70% in the response to the high workload imposed by veratridine, and

  • completely suppressed the OCR responses to moderate (K+-depolarization) and small (carbachol) workloads,
  • effects reverted by pyruvate supply.

For K+-depolarization, this occurs in spite of the presence of large [Ca2+]mit signals and increased reduction of mitochondrial NAD(P)H.

These results show that ARALAR-MAS is a major contributor of Ca2+-stimulated respiration in neurons

  • by providing increased pyruvate supply to mitochondria.

In its absence and under moderate workloads, matrix Ca2+ is unable to stimulate pyruvate metabolism and entry in mitochondria suggesting a limited role of MCU in these conditions.

This article was invited for a Special Issue entitled: 18th European Bioenergetic Conference.    Copyright © 2014. Published by Elsevier B.V.

KEYWORDS:  ATP-Mg/Pi transporter; Aspartate–glutamate transporter; Calcium; Calcium-regulated transport; Mitochondrion; Neuronal respiration PMID: 24820519


Sestrin2 inhibits uncoupling protein 1 expression through suppressing reactive oxygen species.

Ro SH1Nam M2Jang I1Park HW1Park H1Semple IA1Kim M1et al.
Proc Natl Acad Sci U S A. 2014 May 27;111(21):7849-54.
doi: 10.1073/pnas.1401787111.

Uncoupling protein 1 (Ucp1), which is localized in the mitochondrial inner membrane of mammalian brown adipose tissue (BAT), generates heat by uncoupling oxidative phosphorylation. Upon cold exposure or nutritional abundance, sympathetic neurons stimulate BAT to express Ucp1 to induce energy dissipation and thermogenesis. Accordingly, increased Ucp1 expression reduces obesity in mice and is correlated with leanness in humans.

Despite this significance, there is currently a limited understanding of how Ucp1 expression is physiologically regulated at the molecular level. Here, we describe the involvement of Sestrin2 and reactive oxygen species (ROS) in regulation of Ucp1 expression. Transgenic overexpression of Sestrin2 in adipose tissues inhibited both basal and cold-induced Ucp1 expression in interscapular BAT, culminating in decreased thermogenesis and increased fat accumulation.

Endogenous Sestrin2 is also important for suppressing Ucp1 expression because BAT from Sestrin2(-/-) mice exhibited a highly elevated level of Ucp1 expression. The redox-inactive mutant of Sestrin2 was incapable of regulating Ucp1 expression, suggesting that Sestrin2 inhibits Ucp1 expression primarily through reducing ROS accumulation.

Consistently, ROS-suppressing antioxidant chemicals, such as butylated hydroxyanisole and N-acetylcysteine, inhibited cold- or cAMP-induced Ucp1 expression as well. p38 MAPK, a signaling mediator required for cAMP-induced Ucp1 expression, was inhibited by either Sestrin2 overexpression or antioxidant treatments.

Taken together, these results suggest that Sestrin2 and antioxidants inhibit Ucp1 expression through suppressing ROS-mediated p38 MAPK activation, implying a critical role of ROS in proper BAT metabolism.

KEYWORDS: aging; homeostasis; mouse; β-adrenergic signaling      PMID: 24825887     PMCID:  PMC4040599

Mitochondrial EF4 links respiratory dysfunction and cytoplasmic translation in Caenorhabditis elegans.

Yang F1Gao Y1Li Z2Chen L3Xia Z4Xu T5Qin Y6
Biochim Biophys Acta. 2014 May 15. pii: S0005-2728(14)00499-X.
doi: 10.1016/j.bbabio.2014.05.353.

How animals coordinate cellular bioenergetics in response to stress conditions is an essential question related to aging, obesity and cancer. Elongation factor 4 (EF4/LEPA) is a highly conserved protein that promotes protein synthesis under stress conditions, whereas its function in metazoans remains unknown.

Here, we show that, in Caenorhabditis elegans, the mitochondria-localized CeEF4 (referred to as mtEF4) affects mitochondrial functions, especially at low temperature (15°C).

At worms’ optimum growing temperature (20°C), mtef4 deletion leads to self-brood size reduction, growth delay and mitochondrial dysfunction.

Transcriptomic analyses show that mtef4 deletion induces retrograde pathways, including mitochondrial biogenesis and cytoplasmic translation reorganization.

At low temperature (15°C), mtef4 deletion reduces mitochondrial translation and disrupts the assembly of respiratory chain supercomplexes containing complex IV.

These observations are indicative of the important roles of mtEF4 in mitochondrial functions and adaptation to stressful conditions.

Copyright © 2014. Published by Elsevier B.V.

KEYWORDSC. elegans; EF4(LepA/GUF1); Mitochondrial dysfunction; Retrograde pathways; Translation    PMID:  24837196

The metabolite α-ketoglutarate extends lifespan by inhibiting ATP synthase and TOR.

Chin RM1Fu X2Pai MY3Vergnes L4Hwang H5Deng G6Diep S2, et al.
Nature  2014 Jun 19;509(7505):397-401. doi: 10.1038/nature13264. 

Metabolism and ageing are intimately linked. Compared with ad libitum feeding, dietary restriction consistently extends lifespan and delays age-related diseases in evolutionarily diverse organisms. Similar conditions of nutrient limitation and genetic or pharmacological perturbations of nutrient or energy metabolism also have longevity benefits.

Recently, several metabolites have been identified that modulate ageing; however, the molecular mechanisms underlying this are largely undefined. Here we show that α-ketoglutarate (α-KG), a tricarboxylic acid cycle intermediate, extends the lifespan of adult Caenorhabditis elegans.

ATP synthase subunit β is identified as a novel binding protein of α-KG using a small-molecule target identification strategy termed drug affinity responsive target stability (DARTS). The ATP synthase, also known as complex V of the mitochondrial electron transport chain, is the main cellular energy-generating machinery and is highly conserved throughout evolution.

Although complete loss of mitochondrial function is detrimental, partial suppression of the electron transport chain has been shown to extend C. elegans lifespan.

We show that α-KG inhibits ATP synthase and, similar to ATP synthase knockdown, inhibition by α-KG leads to reduced ATP content, decreased oxygen consumption, and increased autophagy in both C. elegans and mammalian cells.

We provide evidence that the lifespan increase by α-KG requires ATP synthase subunit β and is dependent on target of rapamycin (TOR) downstream.

Endogenous α-KG levels are increased on starvation and α-KG does not extend the lifespan of dietary-restricted animals, indicating that α-KG is a key metabolite that mediates longevity by dietary restriction.

Our analyses uncover new molecular links between a common metabolite, a universal cellular energy generator and dietary restriction in the regulation of organismal lifespan, thus suggesting new strategies for the prevention and treatment of ageing and age-related diseases.

PMID: 24828042



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Reporter: Aviva Lev-Ari, PhD, RN

Based on the results of a new study, researchers are developing a clinical trial to test imatinib(Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

VIEW VIDEO by  Mayo Clinic Dr. Tim Call describes Chronic Lymphocytic Leukemia (CLL), its diagnosis, and treatment options for patients with CLL.

VIEW VIDEO  by Leading CLL researcher Dr. Thomas Kipps discusses the latest in the course of the disease including: symptoms, causes, and risk factors. Dr. Kipps also highlights discoveries made in his lab that may lead to developing new therapies to treat this disease. Series: “Stein Institute for Research on Aging” [9/2010] [Health and Medicine] [Show ID: 19345]

Understanding the Molecular Basis of Imatinib Mesylate Therapy in Chronic Myelogenous Leukemia and the Related Mechanisms of Resistance1

Commentary re: A. N. Mohamed et al., The Effect of Imatinib Mesylate on Patients with Philadelphia Chromosome-positive Chronic Myeloid Leukemia with Secondary Chromosomal Aberrations. Clin. Cancer Res., 9: 1333–1337, 2003.

  1. Guido Marcucci2,
  2. Danilo Perrotti, and
  3. Michael A. Caligiuri

+Author Affiliations

  1. Division of Hematology and Oncology, Department of Internal Medicine [G. M., M. A. C.], Division of Human Cancer Genetics, Department of Molecular Virology, Immunology and Medical Genetics [G. M., D. P., M. A. C.], The James Cancer Hospital and The Comprehensive Cancer Center at The Ohio State University, Columbus, Ohio 43210


CML3 is a myeloproliferative disorder with an incidence of approximately 1–1.5 cases/100,000 population/year, a slight male predominance, and a peak between 50 and 60 years of age (1) . This condition arises from a transformed pluripotent hematopoietic precursor associated with t(9;22)(q34;q11.2) that gives rise to the Ph′ chromosome. At the molecular level, this cytogenetic aberration results in the fusion of the ABL gene at chromosome band 9q34 with the BCR gene at chromosome band 22q11.2. The resultantBCR/ABL fusion gene encodes a chimeric protein necessary and sufficient to confer the leukemic phenotype. In a minority of the cases, despite absence of the Ph′ chromosome, molecular methodologies (i.e., fluorescence in situ hybridization, Southern, or RT-PCR) can still detect BCR/ABL as the product of complex cytogenetic aberrations involving other chromosomes in addition to 9q34 and 22q11.2, or cryptic genomic rearrangements of the BCR and ABL genes. Taken all together, >95% of the CML cases are associated with BCR/ABL expression that, therefore, represents the hallmark of this condition.

CML is a bi- or triphasic disease (2) . Patients usually present in a chronic proliferative phase characterized by splenomegaly and accumulation of neutrophils in their various stages of maturation. Basophils and blasts are normally <20% and 10%, respectively, in CP CML. Evolution to the BP (or blast crisis) is defined by an increase (≥20%) in myeloid or lymphoid blasts in blood, BM, or extramedullary locations. In many cases, the transformation is characterized by a passage through an AP, in which the failure of a patient to respond to therapy is accompanied by an increase in percentage of blasts (10–19%); a ≥20% increase in basophils, uncontrolled thrombocytosis, or thrombocytopenia; and acquisition of new cytogenetic abnormalities such as trisomy 8, isochromosome 17q, or a second Ph chromosome and/or genetic inactivation of the p53 gene.

The ultimate goal of treatment for CML is prevention of blast crisis, because, once this occurs, the prognosis is dismal. Although a rapid reduction of the white cell count can be achieved with chemotherapy (i.e., busulfan or hydroxyurea) in CP CML, these drugs usually fail to prevent disease progression. IFN-α was the first agent proven capable of modifying the biological history of CML by prolonging survival in patients who achieved CHR and MCR (<35% of Ph′+cells; Ref. 3 ). A second breakthrough in the treatment of CML occurred when 60–80% of patients undergoing alloBMT in CP were reported to be disease free at 5 years (456) . However, both IFN-α and alloBMT have considerable treatment-induced toxicity that attenuated the initial enthusiasm for these results, and novel, less toxic therapeutic strategies are being explored. In 2001, Druker et al. (7)reported the first Phase I study with imatinib mesylate (STI571, Gleevec), a specific inhibitor of BCR/ABL oncogenic activity. In this study, the authors demonstrated that high rates of CHR and MCR were achieved with relatively few side effects in patients with CML refractory or intolerant to IFN-α, opening new avenues for molecularly targeted therapies in this disease. Subsequently, encouraging results were also obtained for CML patients in BP (8) .

Is BCR/ABLthe Driving Force for Leukemogenesis in CML?

The transforming activity of BCR/ABL has long been demonstrated using in vitro and in vivo models. In initial studies, transfection of the BCR/ABL gene fusion resulted in malignant transformation of normal fibroblasts, and induced independent survival and proliferation in growth factor-dependent cell lines. Expression of BCR/ABL was also shown to be necessary and sufficient to induce leukemogenesis in animal models (reviewed in Ref. 9 ). Expression of BCR/ABL in mice was achieved by either introduction (“knock-in”) of the fusion gene in the mouse genome or by infecting murine stem cells with BCR/ABL-containing retroviral vectors. In knock-in transgenic mice with conditionalBCR/ABL expression, a low penetrance phenotype of acute B- or T-cell leukemia was reported. In contrast, in mice sublethally radiated and transplanted with syngeneic retrovirally transfected BCR/ABL+ stem cells, a condition mimicking human myeloproliferative disorders with neutrophil increase, BM expansion, hepatosplenomegaly, extramedullary hematopoiesis, and pulmonary leukostasis was observed.

How Does BCR/ABL Transform Cells?

The fusion partner ABL is a member of the nonreceptor tyrosine kinase family (10) . This gene encodes a protein containing a tyrosine kinase activity domain (SH1) in addition to two other regulatory domains (SH2 and SH3) that mediate protein-protein interaction and modulate activation of signal transduction. A nuclear localization domain is also present, supporting a shuttling activity of the ABL protein between cytoplasm and nucleus. Genetic disruption of ABL in mice results in lymphopenia, runting, and perinatal mortality. The other fusion partner, BCR, is a protein with multiple functional domains involved in oligomerization, SH-2 binding, serine/threonine kinase activity, and activation of members of the Rho small GTP-ase family of proteins (10) . Structural analysis of this gene suggests a role as a mediator of signaling transduction. With targeted disruption of BCR, mice have increased susceptibility to septic shock, but normal hematopoiesis.

In CML, each of the two partner genes are disrupted at specific breakpoints and fuse to create the chimeric BCR/ABL gene (11) . The most common rearrangements give rise to fusion transcripts identified as b2a2 or b3a2, which, in turn, are translated into a 210 kDa protein. Alternative BCR breakpoints can be located in minor cluster (m-BCR) or micro (μ) cluster (μ-BCR) regions and result in fusion transcripts that encode smaller (190 kDa) or larger (230 kDa) products, respectively. Although usually associated with Ph′+ acute lymphoblastic PiQO leukemia, the protein can also be detected in ≥90% of the CML patients from alternative splicing of p210. p230 is instead usually associated with CML patients presenting with an unusual predominance of neutrophils, resembling chronic neutrophilic leukemia. In each of these BCR/ABL variants, the ABL tyrosine kinase domain autophosphorylates and becomes constitutionally activated. Such BCR/ABLderegulated tyrosine kinase activity is, in fact, responsible for transformation of the hematopoietic stem cell and maintenance of the leukemic phenotype by recruiting and activating transducing signal pathways (i.e., RAS, RAF, extracellular signal-regulated kinase, c-Jun NH2-terminal kinase, phosphatidylinositol 3′-kinase, cCbl, CRKL, Janus-activated kinase-signal transducers and activators of transcription, PKC and PLCγ) involved in: (a) enhanced gene transcription (i.e., c-myc, c-Jun, reviewed in Ref. 12 ); (b) altered mRNA processing, nuclear export, and translation (i.e., bcl-xL, CAAT/enhancer binding protein α, and p53; reviewed in Ref. 13 , 14 ); and (c) increased or decreased protein stability (i.e., Abi proteins; DNA-PKcs; FUS, and hnRNP A1; reviewed in Ref. 13). This, in turn, leads to enhanced proliferative potential and survival, altered motility and trafficking, and suppression of granulocytic differentiation (1 , 13 , 15 , 16) .

Mechanisms of Action of Imatinib Mesylate

BCR/ABL is an ideal target for molecular targeted therapy, because this fusion protein is present in all of the CML cells, is absent from nonmalignant cells, and is necessary and sufficient to induce leukemia. Imatinib mesylate is a 2-phenylaminopyrimidine tyrosine kinase inhibitor with specific activity for ABL, platelet derived growth factor receptor, c-kit, and Albeson-related gene (17) . The pharmacological basis of this interaction has been elucidated by crystallographic studies. Imatinib mesylate binds to the amino acids of the BCR/ABL tyrosine kinase ATP binding site and stabilizes the inactive, non-ATP-binding form of BCR/ABL, thereby preventing tyrosine autophosphorylation and, in turn, phosphorylation of its substrates. This process ultimately results in “switching-off” the downstream signaling pathways that promote leukemogenesis. Preclinical in vitro and in vivo data indicated an impressive selective activity of imatinib mesylate on cells expressing BCR/ABL, and supported a rapid transition of this compound from the bench to the clinic.

To date, imatinib mesylate has been evaluated in several Phase I and II clinical trials of patients with IFN-α-resistant chronic, accelerated, or BP CML (7 , 8 , 181920) . From the collective analysis of these studies, imatinib mesylate appears to effectively induce high CHR and cytogenetic response rates with relatively few side effects. In patients with CP CML who have failed IFN-α the CHR was 95%, MCR 60%, and complete cytogenetic remission 46%. Notably, in these patients achievement of MCR at the 3-month time point correlated with improved progression-free survival. In AP and in blast crisis, the CHRs were 34% and 8%, MCRs were 24% and 16%, and complete cytogenetic remissions were 17%, and 7%, respectively. Disease progression was 11% at 18 months for CP, 40% at 12 months for AP, and 80% at 18 months for BP. Finally, preliminary data from an interim analysis of a phase III study of untreated CML patients randomized between imatinib mesylate versus IFN-α and ARA-C indicate a significantly better CHR, complete cytogenetic remission, and progression-free survival for the imatinib mesylate group after a median follow-up of 14 months (21) . However, a longer follow-up will be necessary to assess whether this compound can also impact on the natural history of the disease and prevent or delay transformation to blast crisis.

Mechanisms of Resistance to Imatinib Mesylate

During disease progression, CML progenitor cells acquire a number of genetic alterations, most probably because of increased genomic instability, that may explain the aggressive phenotype, chemotherapeutic drug resistance, and poor prognosis of CML in BP. Despite the exciting results obtained with imatinib mesylate noted above, CML patients eventually show resistance at a rate of 80% in BP, 40–50% in AP, and 10% in CP post-IFNα failure, at 2 years (19) . Identification of the molecular basis of resistance is important, because it could provide insight into disease progression and into the design of novel therapeutic strategies to prevent and overcome treatment resistance.

CML patients with imatinib mesylate resistance can be stratified into those with primary refractory disease, most frequently in accelerated or BPs, and those who relapse after initial response, who are most frequently in CP. On the basis of the presence or absence of BCR/ABL tyrosine kinase activity in leukemia cells, it is also possible to discriminate between cases with BCR/ABL-dependent and -independent mechanisms of imatinib mesylate resistance. Notably, because the BCR/ABL enzymatic activity cannot be easily measured in blood or BM patient samples, levels of phosphorylation of the BCR/ABL substrate CRKL have been used as a surrogate end point for the tyrosine kinase activity(22) .

In patients with higher levels of CRKL phosphorylation despite treatment with imatinib mesylate, resistance has been found to result from at least three different BCR/ABL-dependent mechanisms: BCR/ABL gene amplification, BCR/ABL mutations, and high plasma levels of AGP (reviewed in Ref. 23 ).

The association of BCR/ABL gene amplification with resistance to imatinib mesylate is consistent with the reliance of CML blast crisis cells on BCR/ABL expression/activity for their proliferation and survival, and with the reported enhanced expression of BCR/ABL in these cells (24) . Indeed, high levels of BCR/ABL expression, which are detected frequently in CML-blast crisis but not CP cells, appear to be required for suppression of myeloid differentiation and increased resistance to chemotherapy-induced apoptosis ofBCR/ABL-expressing cells. Specifically, high levels of BCR/ABL kinase activity are required for hnRNP E2-dependent inhibition of CAAT/enhancer binding protein α, the major regulator of granulocytic differentiation (25) , and for the La-dependent enhancement of MDM2 expression, which, in turn, results in functional inactivation of p53(14) , also required for myeloid blastic transformation (26 , 27) Although the mechanisms underlying such an increase of BCR/ABL expression are unclear, a double Ph′ chromosome is likely to be responsible for the enhanced BCR-ABL levels in some cases.

Other mechanisms of imatinib mesylate resistance involve mutations in the BCR/ABLgene itself. Several different mutations have been detected in at least 13 amino acids of the ATP-binding site or other regions of the tyrosine kinase domain, and the list is growing (23 , 28 , 29) . These mutations usually prevent imatinib mesylate from binding to BCR/ABL, thereby resulting in lack of inhibition of the tyrosine kinase activity. Among these mutations, substitution of a threonine to isoleucine at position 315 of ABL that prevents imatinib mesylate from binding to the ATP-binding domain, is the first described and one of the most frequent (22) .

A third mechanism of resistance relies on plasma levels of AGP. It has been shown that AGP binds imatinib mesylate at physiological concentrations in vitro and in vivo, and blocks the ability of imatinib mesylate to inhibit BCR/ABL kinase activity in a dose-dependent manner (reviewed in Ref. 23 ). Finally, in patients with primary refractoriness to imatinib mesylate, resistance more often occurs in absence of significant CRKL phosphorylation, suggesting activation of BCR/ABL-independent leukemogenic pathways.

In this issue, Mohamed et al. (30) hypothesized that clonal evolution, defined as acquisition of additional cytogenetic abnormalities other than t(9;22)(q34;q11), is a marker for genomic instability, and thereby, in this setting, additional “hits” can occur to activate BCR/ABL-independent leukemogenic mechanisms. Given this premise, CML patients with a more complex karyotype were expected to be more resistant to imatinib mesylate. To test their hypothesis, these authors analyzed 58 BCR/ABL-positive patients with IFN-α-resistant CP (n = 13), AP (n = 24), or BP (n = 21) CML with additional cytogenetic abnormalities who were each treated with imatinib mesylate. Of the 58 patients, 15 (CP = 46%; AP = 25%; BP = 14%) achieved a cytogenetic response, and 12 had a complete cytogenetic remission. With a follow-up of 17–30 months, 7 (12%) remained in complete remission on imatinib mesylate, supporting the notion that a subset of CML patients with t(9;22)(q34;q11) and additional cytogenetic abnormalities can achieve a sustained response. Because the molecular mechanisms of resistance in these patients were not fully evaluated, the contribution of additional cytogenetic abnormalities as an independent predictor of resistance to imatinib mesylate could not be directly addressed. Similar results were also reported in the imatinib mesylate initial studies (18 , 20) , and more recently by Schoch et al. (31) . These authors reported on 31 patients with additional chromosomal abnormalities present before the start of imatinib mesylate therapy. Additional cytogenetic abnormalities were less frequent in chronic than other phases of the disease (35.5% versus 68.8%; P = 0.0008), and when corrected for the difference in disease stage, they did not influence response to imatinib mesylate. These results have been confirmed recently by a larger study reported by Cortes et al. (32) where 498 CML patients in CP or AP were treated with imatinib mesylate. Of the 498, 121 had additional cytogenetic abnormalities. In a multivariate analysis at the 3-month time point, lack of cytogenetic response, but not presence of additional cytogenetic abnormalities, was found to be a negative prognostic factor for survival

Although a longer follow-up is necessary to draw definitive conclusions, these findings suggest that additional cytogenetic aberrations do not appear to impact on disease response, and, therefore, karyotype analysis should not be used to stratify patients for therapeutic alternatives to imatinib mesylate. Furthermore, despite clonal evolution, the oncogenic potential of BCR/ABL appears to remain the driving force for leukemogenesis, and, therefore, may continue to serve as a therapeutic target. Finally, in patients with additional cytogenetic abnormalities who are resistant to imatinib mesylate, evaluation for levels of CRKL-phosphorylation should be done to sort out the nature of the resistance to this treatment and to understand the interplay between BCR/ABL-dependent and -independent mechanisms in disease progression.

Concluding Remarks

The results obtained with imatinib mesylate to date are truly impressive, but longer follow-up will be necessary to establish whether prevention or delay of blast crisis can be achieved and whether an improved overall survival for the majority of patients with CML can be obtained. It is clear that complete cytogenetic remission is achievable in most patients with CP CML, and that those who do not achieve this important end point between 3 and 6 months are likely to have a poor outcome. However, in patients with complete cytogenetic remission, other challenges remain. In these patients, for instance, molecular remission defined as the absence of BCR/ABL fusion transcript by RT-PCR is usually not achieved. The reasons for persistent low levels of residual disease after imatinib mesylate and the prognostic significance of these findings are unknown. It is possible that small numbers of mutated and resistant BCR/ABL-positive subclones remain essentially unaffected by this treatment, and if a proliferation advantage is subsequently acquired in these cells, they may drive disease recurrence. Therefore, in patients with complete cytogenetic remission, monitoring of the BCR/ABL fusion transcript levels by quantitative RT-PCR has been suggested to predict impending relapse, and if rising levels of BCR/ABL expression are detected, consideration could be given to alternative strategies including alloBMT.

However, emerging data support the notion that hematologic or cytogenenetic remission can be achieved in imatinib-relapsed CP CML patients with higher doses of this agent. Kantarjian et al. reported on 54 patients with CML in CP who were initially treated with 400 mg of imatinib mesylate and, subsequently, with a higher dose (i.e., 800 mg) when hematologic or cytogenetic resistance or relapse developed (33) . Among 20 patients treated for hematologic resistance or relapse, 13 (65%) achieved CHR without complete cytogenetic remission, and among 34 patients treated for cytogenetic resistance or relapse, 19 (56%) achieved a complete cytogenetic remission or MCR. However, the mechanisms of resistance to standard dose were not evaluated in these patients and, therefore, correlation of these mechanisms with clinical response to the higher doses was not possible. Nevertheless, these data are intriguing and pose the question of whether a higher dose of imatinib mesylate could be used at the time of the initial diagnosis or during molecular relapse to prevent overt leukemia recurrence or blast transformation. Future studies will no doubt address these important issues. Regardless, it is undeniable that imatinib mesylate has changed our approach to CML and paved the way for additional molecular targeted strategies in leukemia.


  • 1 Supported in part by P30-CA16058, and K08-CA90469 Grants from the National Cancer Institute, Bethesda, MD, The Elsa U. Pardee Cancer Research Foundation, and The Coleman Leukemia Research Foundation.

  • 2 To whom requests for reprints should be addressed, at The Ohio State University, 458A Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. Phone: (614) 293-7597; Fax: (614) 293-7527; E-mail:

  • 3 The abbreviations used are: CML, chronic myelogenous leukemia; Ph′, Philadelphia; ABL, Abelson; RT-PCR, reverse transcription-PCR; BM, bone marrow; CHR, complete hematologic remission; MCR, major cytogenetic response; alloBMT, allogeneic bone marrow transplantation; AGP, α1 glycoprotein; CP, chronic phase; AP, accelerated phase; BP, blastic phase.

  • Received March 3, 2003.
  • Accepted March 3, 2003.

Imatinib May Help Treat Aggressive Lymphoma

Based on the results of a new study, researchers are developing a clinical trial to test imatinib (Gleevec) in patients with anaplastic large cell lymphoma (ALCL), an aggressive type of non-Hodgkin lymphoma that primarily affects children and young adults.

The researchers found that a protein called PDGFRB is important to the development of a common form of ALCL. PDGFRB, a growth factor receptor protein, is a target of imatinib. Imatinib had anticancer effects in both a mouse model of ALCL and a patient with the disease, Dr. Lukas Kenner of the Medical University of Vienna in Austria and his colleagues reported October 14 in Nature Medicine.

The authors decided to investigate the effect of imatinib after finding a link between PDGFRB and a genetic abnormality that is found in many patients with ALCL. Previous work had shown that this genetic change—a translocation that leads to the production of an abnormal fusion protein called NPM-ALK—stimulates the production of two proteins, transcription factors called JUN and JUNB.

In the new study, experiments in mice revealed that these proteins promote lymphoma development by increasing the levels of PDGFRB.

Because imatinib inhibits PDGFRB, the authors tested the effect of the drug in mice with the NPM-ALK change and found that it improved their survival. They also found that imatinib given together with the ALK inhibitor crizotinib (Xalkori) greatly reduced the growth of NPM-ALK-positive lymphoma cells in mice.

To test the treatment strategy in people, they identified a terminally ill patient with NPM-ALK-positive ALCL who had no other treatment options and agreed to try imatinib. The patient began to improve within 10 days of starting the therapy and has been free of the disease for 22 months, the authors reported.

The observation that inhibiting both ALK and PDGFRB “reduces lymphoma growth and alleviates relapse rates” led the authors to suggest that the findings might be relevant to lymphomas with PDGFRB but without the NPM-ALK protein. “Our findings suggest that imatinib is a potential therapeutic option for patients with crizotinib-resistant lymphomas.”

A planned clinical trial will be based on the expression of PDGFRB in tumors.



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