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- Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm
- MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia
Leonidas C. Platanias; Map kinase signaling pathways and hematologic malignancies. Blood ; 12 : —
Revolution of Chronic Lymphocytic Leukemia Therapy: the Chemo-Free Treatment Paradigm
Leonidas C. Platanias; Map kinase signaling pathways and hematologic malignancies. Blood ; 12 : — Mitogen-activated protein Map kinases are widely expressed serine-threonine kinases that mediate important regulatory signals in the cell. Three major groups of Map kinases exist: the p38 Map kinase family, the extracellular signal-regulated kinase Erk family, and the c-Jun NH 2 -terminal kinase JNK family.
The members of the different Map kinase groups participate in the generation of various cellular responses, including gene transcription, induction of cell death or maintenance of cell survival, malignant transformation, and regulation of cell-cycle progression. Depending on the specific family isoform involved and the cellular context, Map kinase pathways can mediate signals that either promote or suppress the growth of malignant hematopoietic cells.
Over the last few years, extensive work by several groups has established that Map kinase pathways play critical roles in the pathogenesis of various hematologic malignancies, providing new molecular targets for future therapeutic approaches. In this review, the involvement of various Map kinase pathways in the pathophysiology of hematologic malignances is summarized and the clinical implications of the recent advances in the field are discussed. The different members of the superfamily of mitogen-activated protein Map kinases participate in signaling cascades conserved through evolution, which regulate important biologic activities.
Map kinase signaling cascades are activated by a variety of different cellular stimuli and mediate diverse responses. Accumulating evidence indicates that an important function of Map kinases is the generation of signals of critical value to the control of normal and malignant hematopoiesis by cytokines and growth factors. The Erk pathway is activated in response to several cytokines and growth factors, and primarily mediates mitogenic and antiapoptotic signals.
In general, Map kinase pathways are activated by various stimuli to regulate, among other things, production of various cytokines and growth factors.
Subsequently, they participate in signaling pathways activated by such cytokines or growth factors to mediate generation of specific biologic responses. Thus, for a given cytokine-dependent response, the function of Map kinases may be critical at 2 steps. The first step involves the biosynthesis and production of the cytokine in response to a stimulus, while the second step involves participation of Map kinases in signaling cascades activated by the cytokine to induce its biologic effects on target cells Figure 1.
Dual roles for Map kinase pathways in the induction of cytokine responses. Regulation of cytokine production and participation in cytokine-dependent signaling cascades. In order for the different Map kinases to be activated by various stimuli, there is a requirement for dual phosphorylation on threonine Thr and tyrosine Tyr residues present in specific motifs ThrXaaTyr for each kinase group.
Schematic generic overview of the sequence of events leading to activation of Map kinase pathways. The activation of different Map kinase signaling cascades by various stimuli is required for induction of various important cellular biologic responses, including phosphorylation of transcription factors and transcriptional regulation, nuclear chromatin remodeling and immediate gene induction, cytokine production, as well as regulation of apoptosis and cell-cycle progression.
Such biologic activities vary with the specific family of Map kinases activated and the distinct stimulus inducing such activation. Thus, multiple and divergent cellular functions are controlled by the activation of various components of Map kinase signaling cascades in response to a large number of stimuli. This raises questions regarding how the specificity of Map kinase—regulated responses occurs.
An important issue revolves around the identity of cellular mechanisms that are in place to prevent cross-talk between the various cascades and to maintain the veracity and specificity of different signals generated by distinct Map kinase groups. It is well established that various cytokines and growth factors that regulate normal hematopoietic cell proliferation and differentiation activate Map kinase signaling pathways to generate their effects.
Among the different hematopoietic growth factors, erythropoietin has been shown to activate, in responsive cell lines or primary hematopoietic progenitors, members of all different Map kinase groups, including Erk, p38, and JNK. In certain cases, the activation of a specific Map kinase pathway may be synergistically induced by a combination of growth factors to promote hematopoietic cell survival and growth.
In addition to their activation by hematopoietic growth factors, Map kinases are activated by cytokines that negatively regulate normal human hematopoiesis. Moreover, the p38 Map kinase cascade plays a critical role in type I interferon signaling, as it is required for regulation of type I IFN—dependent gene transcription, without modifying activation of signal transducer and activator of transcription Stat proteins.
The requirement of the p38 pathway for the generation of the antiproliferative effects of type I interferons ignited further studies, aimed to evaluate the role of this pathway in the generation of the antiproliferative effects of other well known myelosuppressive cytokines.
Importantly, pharmacologic inhibitors of the p38 Map kinase reversed the inhibitory effects of all these different myelosuppressive cytokines on normal human hematopoiesis in vitro. Such a role for p38 in normal hematopoiesis may have implications in the pathogenesis of certain bone marrow failure syndromes, in which suppression of normal hematopoiesis results from overproduction of myelosuppressive cytokines.
Such a hypothesis was recently directly tested in studies using bone marrows from patients with idiopathic aplastic anemia, an acquired bone marrow failure syndrome caused by cytokine overproduction by activated immune cells. Myelosuppressive cytokines that utilize the p38 Map kinase pathway to suppress the growth of human primitive hematopoietic progenitors.
In general, the available evidence to date suggests that different Map kinase pathways play important roles in signaling for hematopoietic growth factors as well as for myelosuppressive cytokines. Such engagement of Map kinases in signaling for various cytokines appears to exhibit regulatory effects on normal human bone marrow hematopoiesis and has prompted extensive studies to define whether Map kinases participate in the regulation of the abnormal hyperproliferative signals seen in malignant hematopoiesis, as discussed below.
It is of interest that a target protein for the Erk pathway is the acute myelogenous leukemia gene product AML1, also called CBFA2 or PEPB2 alpha B , a transcription factor with transforming capacity that is involved in myeloid hematopoietic differentiation. Independently of results observed with cell lines, which may reflect adaptive changes resulting from long-term culture of the leukemia cells, it is clearly established that in the majority of primary acute leukemia cases, the Erk pathway is constitutively activated and mediates mitogenic signals.
Independently of the roles that other signaling pathways may play in the pathophysiology of acute leukemias, pharmacologic targeting of the Erk pathway may be an attractive clinical-translational approach.
Chronic myelogenous leukemia CML results from oncogenic transformation of hematopoietic stem cells by the product of the bcr-abl oncogene, which is generated by the reciprocal translocation between chromosomes 9 and 22, resulting in the fusion of the bcr gene to the c-abl gene. Other studies have examined the role that the Erk pathway plays in the maintenance of survival of malignant lymphocytes from patients with chronic lymphocytic leukemia CLL. In a recent study, it was found that constitutively active Erk was detectable in the peripheral blood of 11 of 11 patients with NK cell leukemia studied.
Treatment of the cells with Mek inhibitors PD and U or overexpression of a dominant-negative form of Mek-1 resulted in apoptosis. Although the role of Erk kinases in mediating mitogenic and antiapoptotic signals in acute leukemia cells is well defined, the roles that members of the p38 and JNK kinase groups play in regulation of growth of acute leukemia blasts are not well established.
A recent report demonstrated a relationship between constitutive activity of JNK in leukemic blasts and treatment failure in acute myelogenous leukemia. However, the development of such approaches is unlikely to be straightforward, as the JNK pathway is also activated by various chemotherapeutic agents, and its function may also be required for the induction of apoptosis by certain agents that are used in the treatment of AML.
Thus, studies to precisely identify the isoforms involved in each of the 2 JNK-dependent responses in AML cells may provide valuable information for the design of new isoform-specific inhibitors with clinical translational potential. There are no reports directly demonstrating a role for constitutive activation of the p38 Map kinase pathway in the pathophysiology of acute leukemias. These findings indicate that the p38 Map kinase pathway plays a negative role in the induction of all- trans retinoic acid responses in acute promyelocytic leukemia and raise the possibility that combined use of all- trans retinoic acid with pharmacologic inhibitors of p38 may prove more effective than ATRA alone in inducing differentiation of APL blasts in vivo.
Similar mechanisms of synergy with pharmacologic inhibitors of p38 may also be applicable for other drugs used in the treatment of acute promyelocytic leukemia. Other studies have shown that, under certain circumstances, the p38 pathway can cooperate with the Erk pathway to mediate cytokine-induced proliferation of AML cells.
The functional roles that the p38 and JNK Map kinase pathways may play in the pathogenesis and pathophysiology of chronic leukemias have also been extensively studied. The roles of the JNK and p38 pathways in the pathophysiology of other leukemias are not well known. There is some evidence implicating constitutive JNK activation in the pathogenesis of human lymphotropic virus HTLV-1 tumorigenesis and indirectly implying a role for this pathway in the pathogenesis of adult T-cell leukemia.
Efforts have also been made to address the potential roles of the JNK and p38 pathways in the pathophysiology of chronic lymphocytic leukemia CLL. However, the Mek inhibitor U had no inhibitory effects on anti-CD20—induced apoptosis despite the fact that it blocked Erk activation, strongly suggesting that Erk is not required for its antileukemic activity.
The difficulty in working with primary tumor samples from patients suffering from lymphomas has been a limiting factor in efforts to uncover the roles that Map kinases may play in the pathogenesis and pathophysiology of these malignancies.
So far, most of the evidence on the putative roles that Map kinases may play in the pathogenesis of lymphomas is based on work with lymphoma-derived cell lines. However, it is difficult to extrapolate from these studies using cell lines whether such effects also occur in primary lymphoma cells. The p38 Map kinase pathway has been implicated in the regulation of interleukin IL production in Burkitt lymphoma cell lines. Map kinase pathways may also play roles in growth factor loops that promote cell proliferation of the malignant cells in Hodgkin disease.
There is now strong evidence implicating aberrant expression of c-Jun and JunB, which are downstream effectors of Map kinase pathways, in the proliferation of malignant Hodgkin lymphoma cells. There is accumulating evidence that several hematopoietic growth factors are present in the bone marrow microenvironment and regulate survival and proliferation of the malignant plasma cells in multiple myeloma.
Thus, various signaling networks are activated by different cytokines, primarily interleukin-6, to regulate the growth of malignant myeloma cells. Because of this, the pathways activated by such cytokines are of critical importance in the pathogenesis of the disease. Such mutations usually occur in patients with advanced stage disease and involve N-Ras and K-Ras mutations. There is accumulating evidence that in addition to interleukin-6, other growth factors also play important roles in the growth of malignant myeloma cells.
One such factor is insulin-like growth factor 1 IGF It is well established that vascular endothelial growth factor VEGF promotes angiogenesis in various models. This has prompted studies to understand the mechanisms of signal transduction of VEGF and the biologic relevance of such signals in multiple myeloma.
Although there is no evidence that the p38 pathway directly promotes the growth of multiple myeloma cells in response to growth factors, there is evidence that it may be doing so indirectly. Map kinase pathways also play important roles in the regulation of apoptosis in malignant myeloma cells. Previous studies have demonstrated that ionizing radiation induces apoptosis of multiple myeloma cells, which is associated with activation of the JNK kinase signaling pathway.
In addition to promoting cell proliferation, interleukin-6 inhibits Fas-induced apoptosis of multiple myeloma cells. Among the agents shown to induce apoptosis of myeloma cells is the farnesyl transferase inhibitor R The demonstration that Map kinase pathways play important roles in the growth of myeloma cells has provided important insights that may lead to future efforts to combine Map kinase inhibitors with other novel therapeutic agents that inhibit myeloma cell growth.
Such a combined use of these inhibitors also resulted in inhibition of growth of drug-resistant myeloma cells through an interleukin-6—independent mechanism. Dramatic advances have occurred over the last few years in the research field of Map kinases in hematologic malignancies. The realization that Map kinase—dependent signaling cascades play important roles in the regulation of apoptosis and growth of malignant hematopoietic cells has led to extensive studies, aimed to characterize the precise mechanisms that are responsible for such effects.
On the other hand, the regulatory effects of the JNK and p38 Map kinase pathways vary, depending on the specific cellular type and possibly the distinct isoforms involved. Importantly, the JNK and p38 pathways appear to also mediate signals responsible for sensitivity or resistance to the effects of various pharmacologic and biologic agents currently in use for the treatment of various hematologic malignancies. The acquired knowledge from all of these efforts has led to the development of specific pharmacologic inhibitors, some of which are now under evaluation in ongoing clinical trials.
It is likely that over the next few years we will observe an exponential growth in the number of translational clinical research efforts, resulting from the rapidly accumulating new information.
The STI paradigm underscores the importance of understanding in detail the molecular and signaling mechanisms responsible for kinase-dependent malignant cell proliferation and has provided an important model for the development of small molecules that target other kinases involved in the pathogenesis of hematologic malignancies. The evidence accumulated so far, on the roles that Map kinases play in hematologic malignancies, points toward certain clinical and basic research directions that may be of importance in the development of new therapeutic approaches.
Clearly, further characterization of the upstream regulatory signals and the downstream effectors for the different Map kinases will help us to better understand the ways in which Map kinases generate their effects. Also, further delineation of the multiple kinases involved in the different Map kinase group cascades may provide more specific targets for translational approaches. There is also a need to better characterize the functional roles that distinct isoforms within each Map kinase group play in the pathogenesis of various hematologic malignancies.
Despite the substantial structural homology among the isoforms in each group, there is evidence that distinct isotypes also exhibit different properties and in some cases may mediate opposing biologic responses. Efforts to define the precise biologic activities mediated by such distinct isotypes in different hematologic malignancies, and to design selective pharmacologic inhibitors that target their distinct kinase domains, may prove valuable in the future.
In the same context, very little is known about the functional roles that Erk 3, Erk5, and Erk7 Map kinases may play in the regulation of malignant hematopoiesis. It is possible that these kinases, which do not belong in any of the classic Map kinase groups, also contribute to the pathogenesis of certain hematologic malignancies, and studies in that direction are warranted. Independently of any new information that will arise from future basic science research efforts, there is already ample evidence to support the further development of clinical studies using pharmacologic inhibitors of known Map kinase pathways.
For instance, the design of trials using Mek inhibitors, alone or in combination with cell-cycle inhibitors, for the treatment of leukemias and multiple myeloma is strongly supported from the available preclinical data.
Similarly, studies of pharmacologic inhibitors of Bcl-2 in leukemias would be important and may lead to the future design of trials combining Mek inhibitors with Bcl-2 inhibitors for the treatment of refractory acute leukemias. Beyond studies with Mek kinase inhibitors, studies using drugs that block p38 Map kinases are likely to be initiated in multiple myeloma patients, based on very recent studies indicating that p38 promotes multiple myeloma cell growth via paracrine secretion of IL-6 and VEGF.
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MicroRNAs mediated regulation of MAPK signaling pathways in chronic myeloid leukemia
Over the last years, targeted anticancer therapy with small molecule inhibitors and antibodies has much replaced chemoimmunotherapy, which has been the gold standard of care for patients with chronic lymphocytic leukemia CLL. Here we give an overview of novel targeted agents used in therapy of chronic lymphocytic leukemia, as well as efforts to overcome resistance development, focusing on approved drugs since they gained high relevance in clinical practice. Novel agents moved to the forefront as a treatment strategy of CLL due to their outstanding efficacy, almost irrespectively of the underlying genetic features. Further success was accomplished with venetoclax, which specifically inhibits anti-apoptotic BCL2 and induces apoptosis of CLL cells. Approved combination treatments such as venetoclax or ibrutinib with obinutuzumab show high responses rates and long remission durations.
A role for antigen in the development of chronic lymphocytic leukemia CLL is strongly suggested by the biased immunoglobulin heavy variable IGHV gene repertoire of the malignant clones, the prognostic implications of IGHV gene mutational status and the identification of subsets of patients with almost identical, stereotyped B-cell receptors BcR , who can also exhibit restricted demographic, biological and clinical features. The prototypic class of innate immune receptors includes the Toll-like receptors TLR 6 which recognize molecular structures that are specific and evolutionarily conserved between pathogens. The central feature of microbe recognition by TLR is the triggering of signaling pathways important for the activation of antigen-presenting cells APC , including B cells. In recent years, the role of TLR in the physiology of B cells has received increasing attention as critical antigen-triggered B-cell differentiation steps have been shown to be influenced by TLR-dependent signals, acting in concert with or superimposed on signals originating from the BcR. Several TLR agonists have been used in clinical trials of CLL patients as adjuvants to improve the efficacy of chemotherapy.
Oncotarget a primarily oncology-focused, peer-reviewed, open access, biweekly journal aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. Its scope is unique. The term "oncotarget" encompasses all molecules, pathways, cellular functions, cell types, and even tissues that can be viewed as targets relevant to cancer as well as other diseases. The term was introduced in the inaugural Editorial , Introducing OncoTarget. Sponsored Conferences. Impact Journals is a member of the Society for Scholarly Publishing.
Disclosures: W. No other disclosures were reported. J Exp Med 1 February ; 2 : e
Here we show a direct correlation between cell surface expression and colocalization of these receptors on CLL B cells. In the absence of CD and CD on the cell surface both receptors were expressed in the cytoplasm. The CD receptor was colocalized with markers of the endoplasmic reticulum, the Golgi apparatus and early endosomes.
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Он не допустит, чтобы какие-то страхи лишили его потенциального клиента. - Друг мой, - промурлыкал он в трубку. - Мне показалось, что я уловил в вашей речи бургосский акцент. Сам я из Валенсии. Что привело вас в Севилью.
Как торговую марку? - Беккер смотрел на него изумленно. Парень был озадачен. - Для имени нужна торговая марка, а не патент. - А мне без разницы.
Очевидно, когда Танкадо умер, рядом находились свидетели. Согласно словам офицера, который отвел Дэвида в морг, некий канадский турист сегодня утром в панике позвонил в полицию и сказал, что у одного японца в парке случился сердечный приступ. Прибыв на место, офицер увидел мертвого Танкадо, рядом с которым находился упомянутый канадец, и тут же по рации вызвал скорую. Когда санитары отвезли тело Танкадо в морг, офицер попытался расспросить канадца о том, что произошло.
Он избранник богов. - В моих руках копия ключа Цифровой крепости, - послышался голос с американским акцентом.
Новые обязанности Сьюзан были засекречены, в том числе и для многих людей в высших эшелонах власти. - Шифры, - задумчиво сказал Беккер - Откуда ты знаешь, с чего начинать. То есть… как ты их вскрываешь.
Вы думаете, он, умирая, до последний секунды переживал за несчастное АНБ. - Распадается туннельный блок! - послышался возглас одного из техников. - Полная незащищенность наступит максимум через пятнадцать минут.
К счастью, Дэвид это обнаружил. Он проявил редкую наблюдательность.
У нее чутье. Ну вот, на Мидж снова что-то нашло. - Если Стратмор не забил тревогу, то зачем тревожиться .
Сьюзан в испуге взглянула на Хейла. Он стоял с безучастным видом, словно происходящее его никак не касалось. И это понятно, - подумала. - Никакой вирус Хейла не волнует, он ведь отлично знает, что происходит с ТРАНСТЕКСТОМ. Но Чатрукьян стоял на .
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