Pathophysiology Of Chronic Myelogenous Leukemia Research Articles

Design, synthesis, and biological evaluations of novel 3-amino-4-ethynyl indazole derivatives as Bcr-Abl kinase inhibitors with potent cellular antileukemic activity.

Breakpoint cluster region-Abelson (Bcr-Abl) kinase is a key driver in the pathophysiology of chronic myelogenous leukemia (CML). Broadening the chemical diversity of Bcr-Abl kinase inhibitors with novel chemical entities possessing favorable target potency and cellular efficacy is a current medical demand for CML treatment. In this respect, a new series of ethynyl bearing 3-aminoindazole based Bcr-Abl inhibitors has been designed, synthesized, and biologically evaluated. The target compounds were designed based on introducing the key structural features of ponatinib, alkyne spacer and diarylamide, into the previously reported indazole II to improve its Bcr-Abl inhibitory activity and overcome its poor cellular potency. All target compounds elicited potent activity against Bcr-AblWT with sub-micromolar IC50 values ranging 4.6-667nM. In addition, certain derivatives exhibited promising potency over the clinically imatinib-resistant Bcr-AblT315I. Among the target molecules, compounds 9c, 9h and 10c stood as the most potent derivatives with IC50 values of 15.4nM, 4.6nM, and 25.8nM, respectively, against Bcr-AblWT. Interestingly, 9h showed 2 folds and 3.6 times superior potency to the lead indazole II and 10c, respectively, against Bcr-AblT315I. Molecular docking of 9h pointed out its possibility to be a type II kinase inhibitor. Furthermore, all compounds, except 9b, showed highly potent antiproliferative activity against the Bcr-Abl positive leukemia K562cell (MTT assay) surpassing the modest activity of lead indazole II. Moreover, the most potent members 9h and 10c exerted potent antileukemic activity against NCI leukemia panel, particularly K562cell (SRB assay) with GI50 less than 10nM, being superior to the FDA approved drug imatinib. Further biochemical hERG and cellular toxicity, phosphorylation assay, and NanoBRET target engagement of 9h underscored its merits as a promising candidate for CML therapy.

Status of Leptin in MBCR-ABL p210 Positive Chronic Myeloid Leukemia Patients Before and After Imatinib Therapy: A Conflicting Scenario

Chronic myelogenous leukemia (CML), a myeoloproliferative disorder, is characterized by the presence of the fusion gene BCR-ABL in hematopoietic cells. Leptin, considered a link between cancer and obesity, has been reported to be actively involved in hemopoiesis and pathophysiology of CML. There are few and conflicting reports about the status of serum leptin levels and recently alteration in leptin has been reported due to imatinib mesylate. Leptin and CRP were estimated in 30 (male: 20; female: 10) newly diagnosed and confirmed MBCR- ABL p210 positive CML patients before and after 3 months of therapy by commercial enzyme linked immunosorbent assays. Leptin levels were compared with 30 (male: 20; female: 10) age matched healthy controls accounting for the differences due BMI and gender. Leptin/BMI ratio was significantly raised in both male and female chronic phase patients as compared to controls (p < 0.001, p = 0.048) and accelerated phase patients as compared to controls (males, p < 0.001; females, p < 0.001). The normal gender difference and dependence on BMI was lost in patients. In patients, who failed to achieve hematological baseline, leptin/BMI was higher only in male patients (p = 0.012). Leptin/BMI also correlat- ed with TLC and blast percentage (TLC, R2 = 0.412, p = 0.001; Blast %, R2 = 0.408, p < 0.001). There was no correlation between leptin and CRP levels. Levels decreased significantly after complete hematological remission in both males and females (p = 0.001, p = 0.028). Levels after 3 months of imatinib therapy were significantly higher than controls in all patients not in remission (males, p < 0.001; females, p = 0.018) but only in male patients in re- mission (p = 0.002). Leptin levels were increased in CML patients. The findings suggest a possible role of leptin in patho- genesis of CML or disease progression independent of inflammatory state or reactionary rise. Imatinib itself may increase leptin levels, and, as leptin plays an active role in the pathophysiology of CML, this conflicting scenario needs further investigation. Alterations in leptin need to be investigated cautiously accounting for confounding and differences due to BMI and gender.

Historique de la leucémie myéloïde chronique : un paradigme de traitement du cancer

During two centuries, advances in medicine and medical research have helped to understand the pathophysiology of chronic myelogenous leukemia (CML). This hematologic malignancy is a unique model of oncogenesis where a single molecular hit, causing cell proliferation and survival, was identified. The chromosomal abnormality first highlighted by P. Nowell and D. Hungerford in 1960, and characterized as the reciprocal translocation t(9;22)(q34;q11), the Philadelphia chromosome, discovered in leukemic cells, by J. Rowley in 1973. At the end of the 20th century, the contribution of molecular biology techniques was crucial by the discovery of the BCR-ABL1 hybrid oncogene derived from the t(9;22), responsible for the translation of an aberrant protein tyrosine kinase. This BCR-ABL1 kinase deregulates signaling pathways that control normal cell cycle and survival in primitive hematopoietic cells and is thus responsible for malignant cell accumulation observed in CML. It was then only necessary to develop a targeted treatment adapted to this molecular hit. Recently, tyrosine kinase inhibitors, by their specific inhibitory activity of BCR-ABL, have revolutionized the treatment of CML, allowing rates of haematological, cytogenetic and molecular responses never seen to date, and has significantly improved the overall survival and the quality of life of patients.

An Extended Mathematical Model of Pathophysiology and Response to Treatment in Chronic Myelogenous Leukemia

Chronic myelogenous leukemia (CML) is a malignant clonal disorder of hematopoietic stem cells that results in increase in myeloid, erythroid cells, and platelets in the peripheral blood and marked myeloid hyperplasia in the bone marrow. This disorder is characterized by the specific cytogenetic abnormality, the Philadelphia (Ph) chromosome, which results from a balanced translocation between the long arms of chromosomes 9 and 22, generating the bcr/abl chimeric gene that expresses an abnormal fusion protein with altered tyrosine kinase activity. Imatinib mesylate (IM, Gleevec, Novartis, Basel, Switzerland), is a potent and selective competitive inhibitor of the BCR-ABL protein tyrosine kinase and has shown to induce a high rate of cytogenetic and hematologic response in patients with chronic phase (CP) CML both as initial therapy and as secondary therapy after previous interferon therapy failed. Because the pathophysiology of CML and the mechanism for the clinical effects by IM is relatively uniform among patients, simplification and generalization with mathematical models have been proposed and they have excellently simulated the regression of leukemic cells by IM therapy and the regrowth of CML cells after appearance of IM-resistant clones. These models are based on the assumption that the transition rate of leukemic stem cells or precursor cells to more differentiated fractions are profoundly diminished by the administration of IM. This assumption is sufficient to explain the response as long as the observation period is short. In contrast, the issue regarding the influence of IM on the self-reproduction rate of leukemic stem cells was not focused on in these models because this issue had little effect on short-term outcomes with IM. After a decade since the appearance of IM, accumulated observations of CML patients treated with IM revealed long-term effectiveness; novel transformations to accelerate phase or blastic crisis are rarely observed in patients who continue to receive 400mg/day of IM for five or six years. Our aim is to clarify the effect of IM on leukemic stem cell fractions by extending and modifying the existing models so that they are compatible with actual long-term outcomes of IM therapy. First, we demonstrated that sustained effectiveness of IM for over six years cannot be achieved unless a stem cell fraction of CML is decremented by IM. In order to estimate the degree of stem cell attack by IM, we computed the rate of novel generation of IM-resistant clones before and after IM administration. In this model, we presumed that this rate is proportional to the accumulated number of self-duplication of leukemic stem cells. In order to simulate the actual observation that the clonal evolution decrease annually after IM administration, we illustrated that the rate of self duplication is depleted to at one fourth or less with IM compared to without IM. With this simulation, we show that the tyrosine kinase inhibitors can eradicate malignant cells thus leading to the radical cure of the disease. We also showed that the achievement of major molecular response (MMR; defined as at least three-log reduction of bcr/abl positive clones in the peripheral blood) at the 18th month of IM therapy is roughly associated with the absence of resistant clones at the moment of IM administration, and is obviously linked to successful therapy of CML after IM therapy is launched. This provides the supportive evidence of the previously reported observation that MMR at 18th month is associated with long-term effectiveness. Our model underscores the significance of prompt elimination of leukemic stem cells in order to diminish the generation of novel resistant clones and accomplish complete cure of CML. Development of the evaluation system to quantify residual leukemic stem cells would verify this hypothesis and pursuit to maximal response including early administration of second-generation tyrosine kinase inhibitors would be justified.

Important Therapeutic Targets in Chronic Myelogenous Leukemia

Review the state-of-art knowledge of the biology and therapy of chronic myelogenous leukemia (CML). A review of the literature was undertaken to summarize current information on the pathophysiology of CML and to update data of imatinib mesylate therapy, mechanisms of resistance, and in vitro and clinical data with the new tyrosine kinase inhibitors. Imatinib, which targets the ABL kinase activity of BCR-ABL, has prolonged survival in CML. Despite the efficacy of imatinib, some patients in chronic phase and more in advanced phases of CML develop resistance, frequently as a result of BCR-ABL tyrosine kinase domain mutants that impair imatinib binding but retain enzymatic activity. New tyrosine kinase inhibitors inhibit BCR-ABL more potently than imatinib and maintain activity against an array of imatinib-resistant BCR-ABL mutants. The IC(50) values of nilotinib and dasatinib are at least 10- to 100-fold lower for BCR-ABL compared with imatinib. Phase I-II trials of nilotinib and dasatinib showed high activity in imatinib-resistant CML and Philadelphia chromosome-positive ALL. Dasatinib also inhibits members of the Src family of kinases (SFKs); nilotinib does not. Whether SFKs have a critical role in imatinib resistance or BCR-ABL-mediated oncogenesis is unresolved. Agents that target signals downstream of BCR-ABL (e.g. Ras/Raf and phosphatidylinositol 3-kinase) are under investigation. Understanding the pathophysiology of CML and mechanisms of resistance has produced effective targeted strategies for imatinib-resistant CML.

Chronic Myelogenous Leukemia: From Molecular Biology to Clinical Aspects and Novel Targeted Therapies

The critical causative event in chronic myelogenous leukemia (CML) is the fusion of the head of the bcr gene with the body of the abl gene, named bcr/abl gene. This chimeric BCR/ABL molecule transforms primary myeloid cells to leukemic cells and induces a CML-like disease in mice. The mouse CML model expressing the BCR/ABL molecule has provided important new insights into the molecular pathophysiology of CML and has directly answered many questions regarding this disease. Furthermore, numerous clinical studies have demonstrated a correlation between leukemic clinical features and the position of the breakpoint in the BCR gene of the chimeric BCR/ABL gene. Understanding of the molecular pathogenesis of CML has led to the development of several novel therapies. The BCR/ABL molecule is unique oncogeneiety, having ABL tyrosine kinase activity, making it an ideal target for drug development. Subsequent clinical studies now realize the hypothesis that selective inhibition of the abl tyrosine kinase activity using imatinib mesylate might be useful for the treatment of CML. This article reviews the history of BCR/ABL molecular biology, including the CML model mouse, clinical molecular studies and the recent findings of imatinib mesylate and more potent tyrosine kinase inhibitors developed for the treatment of CML.

Transgenic Mouse Models of BCR/ABL-Positive Chronic Myelogenous Leukemia: A Review

There are three methods for making chronic myelogenous leukemia (CML) mouse models: xenotransplantation of primary Ph-positive CML cells into immunodeficient mice, BCR/ABL-expressing transgenic mice, and BCR/ABL retroviral bone marrow transduction and transplantation. These animal models have provided us with important new insights into the molecular pathophysiology of CML and answered directly many questions regarding this disease. To date, The model mice using the BCR/ABL retroviral bone marrow transduction and transplantation method has provided the most valuable knowledge compared with the other two methods. After a long history of failure, however, recent studies have reported successful establishment of making the CMLphenotype in transgenic mice. The transgenic CML mouse model now appears to be more accurate, informative and advantageous model for studying CML. This article reviews the history of BCR/ABL-expressing CML mouse models and the recent findings in the transgenic mice with the CML-phenotype. Keywords: chronic myelogenous, cml-phenotype, bcr, abl

STAT5 and STAT5A Signaling Play an Important Role in the Pathophysiology of the CML-Like Myeloproliferative Disorder in Mice.

Although numerous studies have implicated signal transducers and activators of transcription (STAT)5 in Bcr/Abl-dependent transformation and survival, the role of STAT5 in chronic myelogenous leukemia (CML) has not been fully elucidated. In mice, the CML-like myeloproliferative disorder can occur in the absence of STAT5A/5B, but the repopulating and colony-formation defects of STAT5A/5B double knockout (−/−) bone marrow (BM) cells have made it difficult to separate Bcr/Abl-specific and Bcr/Abl-non-specific effects. To clarify the role of STAT5 signaling in P210BCR/ABL leukemogenesis, we have expressed Bcr/Abl in primary murine STAT5A-deficient (−/−) BM cells, which have no demonstrable intrinsic hematopoietic defects. Interestingly, the absence of STAT5A profoundly decreased the incidence of the pure CML-like disease. Only 24% of wild-type mice reconstituted with P210-transduced STAT5A(−/−) BM cells developed CML, compared to 93% of P210-STAT5A(+/+)- and 83% of P210(+/−)-reconstituted mice. The remainder of P210-STAT5A(−/−)-reconstituted mice developed an acute lymphoblastic leukemia (ALL)-like disease (20%) or a CML/ALL mix (56%), underscoring the relative importance of STAT5 signaling in P210-induced myeloid leukemia compared to P210-induced lymphoid leukemia. There was also a trend for increased latency of the CML-like disease in P210-STAT5A(−/−)-reconstituted mice, with P210-STAT5A(−/−)-reconstituted mice having a median survival of 38 days, compared to only 22 days for P210-STAT5A(+/+) animals. Compared to P210-control cells, primary leukemia cells from P210-STAT5A(−/−) mice had decreased constitutive expression of the STAT5 target genes Bcl-XL and oncostatin M, but preserved expression of pim-1 and cis. Of mice that developed CML, P210-STAT5A(−/−)-reconstituted animals had greater splenomegaly and tended to have higher Bcr/Abl expression than P210-control animals, suggesting that enhanced expression of Bcr/Abl might compensate for the absence of STAT5A in these mice. Importantly, there was no difference in the number of unique P210-STAT5A(−/−) or P210-STAT5A(+/+) leukemic clones by Southern blot, indicating that the reduced incidence of CML in STAT5A (−/−) mice was not due to the decreased availability of CML progenitors. Altogether, these findings indicate that STAT5, particularly STAT5A, plays an important role in the efficient induction of the CML-like disease in mice. A greater understanding of the STAT5 target genes important in CML will provide important insights into the pathophysiology of CML, and may provide additional molecular targets for CML therapy.

Bcr/Abl, leukemogenesis, and genomic instability: a complex partnership

For many years, the issue of genomic instability in chronic myelogenous leukemia (CML) has been one of “guilt by association”. Even before much of the molecular pathophysiology of CML was known, investigators had noted that patients with advanced CML acquired additional cytogenetic abnormalities. Interestingly, there is a relatively short list of common secondary chromosomal cytogenetic changes, including an additional copy of the Philadelphia chromosome, trisomy 8, trisomy 19, isochromosome 17q, and loss of the Y chromosome [1]. Transgenic mice expressing the P190 form of BCR/ABL have also been shown to develop karyotypic abnormalities during the later stages of their leukemic illness, most commonly trisomy involving chromosomes 12, 14, or 17, alone or in combination [2]. Prolonged expression of the P210 form of BCR/ABL in the murine myeloid cell line 32D has been demonstrated to be associated with the development of aneuploidy and complex chromosomal translocations [3]. These and other findings have led investigators to postulate that Bcr/Abl expression itself might be responsible to such secondary genetic changes. Proving such a connection, however, is a complex challenge. Solid tumors often demonstrate a variety of cytogenetic abnormalities [4], most of which are likely the consequence, rather than the cause, of malignant transformation. Therefore, it is conceivable that the additional cytogenetic abnormalities seen in CML could merely reflect stochastic changes due to a prolonged leukemia process. Alternatively, given the impact of Bcr/Abl on factors regulating cell survival, apoptosis, and DNA repair, the hypothesis that Bcr/Abl itself could lead to genomic instability independent of its leukemogenic effect is of considerable interest. One recent approach to this question has been to mate P190BCR/ABL transgenic mice [5] with the transgenic strain

Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios.In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity.In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented.In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control.In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies

AbstractOver the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-α) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios.In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity.In Section II, Dr. Tura, addresses important questions in the use of IFN-α for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented.In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control.In Section IV Drs. Kantarjian and Talpaz review the results of IFN-α plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-α produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-α. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-α and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Chronic Myelogenous Leukemia: Disease Biology and Current and Future Therapeutic Strategies.

Over the last 2 decades, four major therapeutic approaches have drastically changed the prognosis in chronic myelogenous leukemia (CML): 1) allogeneic stem cell transplant (SCT); 2) interferon alpha (IFN-alpha) based regimens; 3) donor lymphocyte infusions (DLI); and 4) and the revolutionary BCR-ABL tyrosine kinase inhibitors such as STI571 (signal transduction inhibitor 571). Each modality has exploited and targeted different aspects of CML biology, and is associated with different risk-benefit ratios. In Section I of this review, Dr. Melo reviews the molecular pathophysiology of CML and potential new targets for therapy including anti-sense strategies to disrupt the BCR-ABL gene and inhibition of the BCR-ABL tyrosine kinase activity. In Section II, Dr. Tura, addresses important questions in the use of IFN-alpha for the treatment of CML, including the mechanism of action and the development of resistance, the optimal dose and duration of therapy and the prediction of response based on clinical features. An approach to the choice of therapy based on the predicted mortality is presented. In Section III Dr. Giralt presents an update on the results of unrelated donor transplantion, donor lymphocyte infusions (DLI) and non-ablative stem cell transplantation (NST) in CML. The roles of CD8-depletion, dose escalation and the transduction of suicide genes in treatment with DLI are addressed. Early results of NST in CML show that it is feasible and can result in long-term disease control. In Section IV Drs. Kantarjian and Talpaz review the results of IFN-alpha plus low-dose cytosine arabinoside and other promising modalities for CML including homoharringtonine, decitabine, and polyethylene glycol-interferon. In Section V they present an update on the recent experience with STI571. Objective but transient responses have been seen in 40% to 50% of patients in CML blastic phase. In accelerated phase, the response rate with STI571 exceeds 70%, and these responses are durable. In chronic phase CML, STI571 at 300 mg daily in patients who failed IFN-alpha produces a complete hematologic response (CHR) in over 90% of patients. Early results suggest cytogenetic response rates of approximately 50%, which may be major in approximately 30%. The maturing results with STI571 may soon change current recommendations regarding the relative roles of established modalities such as allogeneic SCT and IFN-alpha. Important questions include 1) whether STI571 therapy alone may be sufficient to induce long-term survival and event-free survival in CML, or whether it needs to be combined simultaneously or sequentially with IFN-alpha and cytosine arabinoside; and 2) what should the indications for frontline allogeneic SCT be in relation to STI571 therapy.

Chronic Myelogenous Leukemia: From Pathogenesis to Therapy

CHRONIC MYELOGENOUS LEUKEMIA (CML) is a malignancy of the hematopoietic stem cell (HSC) (1) characterized by the Philadelphia chromosome (Ph) (2). The Ph is the result of a translocation between chromosomes 9 and 22, resulting in the formation of a hybrid BCR/ABL gene on chromosome 22 (3). The p210BCR/ABL oncoprotein is necessary and sufficient for transformation. Introduction of BCR/ABL into hematopoietic cell lines renders them cytokine independent in vitro and tumorigenic in vivo (4,5). Transplantation of BCR/ABL-transduced murine HSC causes a CML-like syndrome (6±8), and transgenic expression of BCR/ABL induces leukemias and lymphomas (9,10). Although these studies show the transforming potential of BCR/ABL, they do not explain the typical clinical features of CML. The clinical syndrome of CML can be summarized as an (a) abnormal, unregulated expansion of Ph1 progenitors and precursors (b) affecting the myeloid but not erythroid or lymphoid lineages, (c) which circulate prematurely in the peripheral blood and home to extramedullary locations and (d) demonstrate a tendency to acquire additional molecular defects, leading to blast crisis over a period of 3±5 years (11,12). In this article, we review the molecular pathways that are affected by the BCR/ABL oncoprotein and how this may explain the clinical features of the disease. We also discuss ongoing and future therapeutic approaches for CML that are based on our current understanding of the pathophysiology of CML.

Pathophysiology of CML: Do defects in integrin function contribute to the premature circulation and massive expansion of the BCR/ABL positive clone?

Hematopoiesis takes place in close contact with the marrow microenvironment. Normal progenitors adhere through a variety of receptors to stroma and extracellular matrix components, including fibronectin. Adhesion through β1-integrin receptors to fibronectin not only anchor progenitors to the stroma but also result in direct adhesion-mediated signaling that inhibits progenitor proliferation. In contrast to normal hematopoiesis, chronic myelogenous leukemia (CML) is characterized not only by abnormal, premature circulation of primitive progenitors in the blood but also by continuous progenitor proliferation. Although CML progenitors express the same integrin receptors as normal progenitors, they fail to adhere to stroma and fibronectin, suggesting structural or functional abnormalities of these receptors. Furthermore, CML cells present in contact with stroma or fibronectin continue to proliferate, suggesting that failure to adhere through integrin receptors may also underlie the abnormal proliferation of CML progenitors. The observation that integrin-mediated adhesion and proliferation-inhibitory signaling can be restored through treatment with interferon-α or an activating anti-β1-integrin antibody suggests a functional rather than structural defect that may be related to the presence of the BCR/ABL gene rearrangement in these cells. Insights into the role of integrins as adhesion molecules but also receptors that instruct hematopoietic progenitors to survive, proliferate, and possibly differentiate will not only further our understanding of the normal hematopoietic process but also provide insights into diseases characterized by deranged adhesion and proliferation that may lead to novel therapeutic approaches.