Restoration of INK4a/ARF gene inhibits cell growth and cooperates with imatinib mesylate in Philadelphia chromosome-positive leukemias.
Oncol Res. 2013;21(1):23-31
Authors: Bai Y, Lu Z, Lin Y, Sun B, Wang S, Wang G
VSV-G-pseudotyped lentiviral vectors expressing p16(INK4a) or p14(ARF) were used to infect at high-efficiency Philadelphia chromosome (Ph)-positive leukemia cell lines lacking endogenous transcripts. Restoration of p16(INK4a) accumulated cells in the G0/G1 phase of cell cycle and restoration of p14(ARF) induced their apoptosis, followed by significant growth inhibition. Transduction of primary blast cells from chronic myeloid leukemia in blast crisis (CML-BC) and Ph-positive acute lymphoblastic leukemia (ALL) with p16(INK4a) or p14(ARF) virus also resulted in cell growth inhibition and/or apoptosis with a patient-to-patient variation, whereas clonal growth and differentiation of cord blood progenitor cells were not affected by enforced expression of INK4a/ARF. Furthermore, upon viral transduction at low multiplicity of infection, INK4a/ARF potentiated the effect of imatinib mesylate on Ph-positive leukemia cell lines in an additive but not synergistic manner. These results suggest that INK4a/ARF protein-mimetic agents may be promising options for Ph-positive leukemias in combination with imatinib mesylate.
PMID: 24330849 [PubMed - indexed for MEDLINE]
Detection of BCR-ABL using one step reverse transcriptase- polymerase chain reaction and microchip electrophoresis.
Methods. 2013 Dec 15;64(3):250-4
Authors: Lin X, Wu J, Liu W, Li H, Wang Z, Lin JM
One-step reverse transcriptase polymerase chain reaction (RT-PCR) coupled with microchip electrophoresis (MCE) was established to analyze BCR-ABL fusion gene. The use of one-step RT-PCR could simplify the RT-PCR procedure and thus reduced the risk of contamination and sample consumption. This method also enhanced the sensitivity for amplified target DNA and dramatically shorted the analysis time. Moreover, this assay can simultaneously identify b2a2 and b3a2. Orthogonal array design, which can investigated mutual effects of PCR parameters, was used to optimize the reaction system. This approach was highly effective, reproducible and sensitive, and would be suitable for the determination of BCR-ABL in clinic diagnosis.
PMID: 23748110 [PubMed - indexed for MEDLINE]
Optic Coherence Tomography of Foveal Hemorrhage Associated With Chronic Myelogenous Leukemia.
Retina. 2014 Jul 18;
Authors: Hori S, Yamamoto K
PMID: 25046396 [PubMed - as supplied by publisher]
Clinical advances in the management of chronic myelogenous leukemia: focus on bosutinib and patient considerations.
Patient Prefer Adherence. 2014;8:981-6
Authors: Sweet K, Pinilla-Ibarz J, Zhang L
The treatment for chronic myeloid leukemia has changed significantly over the past 15 years, and as of now, there are five BCR-ABL1 (breakpoint cluster region-Abelson murine leukemia viral oncogene homolog 1) tyrosine kinase inhibitors that have gained approval for treatment of this disease. All five are very effective drugs, and the decision surrounding which to use in specific patients is based on numerous factors. Bosutinib is one of the newer tyrosine kinase inhibitors to gain approval, and has been studied in the first-line setting as well as after failure of other tyrosine kinase inhibitors. It is an SRC-ABL1 (steroid receptor co-activator-ABL1) inhibitor that works in the presence of most kinase domain mutations. The primary side effects of bosutinib are gastrointestinal upsets. In the appropriate clinical setting, bosutinib can be considered a valuable addition to the armamentarium of treatments available for chronic myeloid leukemia.
PMID: 25045255 [PubMed]
5-(2-carboxyethenyl) isatin derivative induces G2/M cell cycle arrest and apoptosis in human leukemia K562 cells.
Biochem Biophys Res Commun. 2014 Jul 17;
Authors: Zhou Y, Zhao HY, Han KL, Yang Y, Song BB, Guo QN, Fan ZC, Zhang YM, Teng YO, Yu P
Our previous study successfully identified that the novel isatin derivative (E)-methyl 3-(1-(4-methoxybenzyl)-2,3-dioxoindolin-5-yl) acrylate (HKL 2H) acts as an anticancer agent at an inhibitory concentration (IC50) level of 3 nM. In this study, the molecular mechanism how HKL 2H induces cytotoxic activity in the human chronic myelogenous leukemia K562 cells was investigated. Flow cytometric analysis showed that the cells were arrested in the G2/M phase and accumulated subsequently in the sub-G1 phase in the presence of HKL 2H. HKL 2H treatment down-regulated the expressions of CDK1 and cyclin B but up-reguated the level of phosphorylated CDK1. Annexin-V staining and the classic DNA ladder studies showed that HKL 2H induced the apoptosis of K562 cells. Our study further showed that HKL 2H treatment caused the dissipation of mitochondrial membrane potential, activated caspase-3 and lowered the Bcl-2/Bax ratio in K562 cells, suggesting that the HKL 2H-causing programmed cell death of K562 cells was caused via the mitochondrial apoptotic pathway. Taken together, our data demonstrated that HKL 2H, a 5-(2-Carboxyethenyl) isatin derivative, notably induces G2/M cell cycle arrest and mitochondrial-mediated apoptosis in K562 cells, indicating that this compound could be a promising anticancer candidate for further investigation.
PMID: 25044115 [PubMed - as supplied by publisher]
Diabetes Insipidus in Myelodysplastic Syndrome: What We learnt from A Case Regarding Its Diagnosis, Pathophysiology, and Management.
Leuk Lymphoma. 2014 Jul 21;:1-9
Authors: Chuang C, Parnerkar V, Radulescu A, Hunt MA, Cayci Z, Ustun C
PMID: 25039352 [PubMed - as supplied by publisher]
Exposure of CML Cells to Imatinib Results in the Post-Transcriptional Induction of Manganese Superoxide Dismutase.
Leuk Lymphoma. 2014 Jul 21;:1-13
Authors: Reinke EN, Bera S, Diamond AM
ABSTRACT The treatment of chronic myelogenous leukemia with specific tyrosine kinase inhibitors typically results in clinical success although therapeutic failure frequently occurs. In order to investigate the biological consequences of treating CML cells with such drugs, we previously reported that the anti-oxidant selenoprotein GPx-1 was induced by imatinib in both patient samples and cultured cells. Here, we extend these findings to demonstrate that the treatment of CML cell lines, but not non-CML cells, results in the approximately 4-fold increase in the levels of another important anti-oxidant protein, MnSOD without altering the steady state levels of the corresponding transcript.
PMID: 25039350 [PubMed - as supplied by publisher]
[Chronic myeloid leukemia stem cells: cross-talk with the niche].
Med Sci (Paris). 2014 Apr;30(4):452-61
Authors: Chomel JC, Aggoune D, Sorel N, Turhan AG
The physiological hematopoietic niche located in bone marrow is a pluricellular structure whose components are now well identified. Within this microenvironment, hematopoietic stem cells are in direct contact with mesenchymal stromal cells, osteoblasts and sinusoidal endothelial cells. These close relationships drive specialized cellular functions (proliferation/quiescence, differentiation/self-renewal) ensuring an efficient hematopoiesis. Chronic myeloid leukemia (CML) is a major model of leukemic hematopoiesis. The BCR-ABL1 tyrosine kinase, constitutively activated in CML, plays a critical role in the pathogenesis of the disease. An intensive cross-talk between CML progenitors and the components of the hematopoietic niche has recently been demonstrated. Consequently, the occurrence of the so-called leukemic niche promotes both the proliferation of myeloid cells and the maintenance of quiescent leukemic stem cells. This bone marrow niche could also protect CML stem cells from tyrosine kinase inhibitors and probably contribute to their resistance towards targeted therapies.
PMID: 24801043 [PubMed - indexed for MEDLINE]
Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management.
Am J Hematol. 2014 May;89(5):547-56
Authors: Jabbour E, Kantarjian H
DISEASE OVERVIEW: Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1-2 cases per 100,000 adults, and accounts for ?15% of newly diagnosed cases of leukemia in adults.
DIAGNOSIS: CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2. This rearrangement is known as the Philadelphia chromosome. The molecular consequence of this translocation is the generation of a BCR-ABL fusion oncogene, which in turn translates into a Bcr-Abl oncoprotein.
FRONTLINE THERAPY: Three tyrosine kinase inhibitors (TKIs), imatinib, nilotinib, and dasatinib have been approved by the US Food and Drug Administration for the first-line treatment of patients with newly diagnosed CML in chronic phase (CML-CP). Clinical trials with second generation TKIs reported significantly deeper and faster responses; their impact on long-term survival remains to be determined.
SALVAGE THERAPY: For patients who fail frontline therapy, second-line options include second and third generation TKIs. Although second and third generation TKIs are potent and specific BCR-ABL TKIs, they exhibit unique pharmacological profiles and response patterns relative to different patient characteristics, such as patients comorbidities, disease stage, and BCR-ABL mutational status. Patients who develop the T315I “gatekeeper” mutation display resistance to all currently available TKIs except ponatinib. Allogeneic transplantation remains an important therapeutic option for CML-CP who have failed at least 2 TKIs, and for all patients in advanced phase disease.
PMID: 24729196 [PubMed - indexed for MEDLINE]
Ponatinib: A new tyrosine kinase inhibitor for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia.
Ann Pharmacother. 2013 Nov;47(11):1540-6
Authors: Shamroe CL, Comeau JM
OBJECTIVE: To review the pharmacology, pharmacokinetics, clinical trials, adverse effects, and formulary considerations of ponatinib, a pan-tyrosine kinase inhibitor (TKI).
DATA SOURCES: A literature search of articles published between January 1966 and June 2013 was performed using PubMed with the following search terms: ponatinib, AP24534, and Iclusig. ARIAD Pharmaceuticals, Inc, was contacted for unpublished information. Other sources included American Society of Hematology abstracts, the Food and Drug Administration Center for Drug Evaluation and Research Web site, and clinicaltrials.gov.
STUDY SELECTION/DATA EXTRACTION: Included articles and abstracts were published in English and contain information about ponatinib, particularly in the treatment of chronic myeloid leukemia (CML) or Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL).
DATA SYNTHESIS: Following the phase II PACE trial, ponatinib was approved for the treatment of patients with chronic-phase (CP), accelerated-phase (AP), or blast-phase (BP) CML or Ph+ ALL who have become intolerant or resistant to previous therapy. Unlike other BCR-ABL TKIs, ponatinib was designed to overcome the T315I mutation. At 15.3 months, 46% of patients with CP-CML achieved a complete cytogenetic response, and 34% achieved a major molecular response. Complete hematologic responses occurred in 47% of patients with AP-CML, 21% with BP-CML, and 34% with Ph+ ALL after 1 year. Severe toxicities included myelosuppression, hepatotoxicity, pancreatitis, and arterial thrombosis.
CONCLUSIONS: Ponatinib is a potent TKI that can overcome several resistance mechanisms in previously treated patients with CML and Ph+ ALL. Ponatinib should be reserved for patients who have failed first-line therapy, have the T315I mutation, or have progressed.
PMID: 24265264 [PubMed - indexed for MEDLINE]
Imatinib-associated melanosis of the palate.
Am J Hematol. 2014 May;89(5):564
Authors: Roeker LE, Wolanskyj AP
PMID: 24030927 [PubMed - indexed for MEDLINE]
Prognostic Significance of the Lymphoblastic Leukemia-Derived Sequence 1 (LYL1) GeneExpression in Egyptian Patients with AcuteMyeloid Leukemia.
Turk J Haematol. 2014 Jun;31(2):128-35
Authors: El-Menshawy N, Shahin D, Ghazi HF
Objective: Aberrant activation of transcription factor genes is the most frequent target of genetic alteration in lymphoid malignancies. The lymphoblastic leukemia-derived sequence 1 (LYL1) gene, which encodes a basic helix-loop helix, was first identified with human T-cell acute leukemia. Recent studies suggest its involvement in myeloid malignancies. We aimed to study the expression percent of oncogene LYL1 in primary and secondary high-risk myeloid leukemia and the impact on prognostic significance in those patients. Materials and Methods: Using quantitative real-time polymerase chain reaction for detection of LYL1 oncogenes, our study was carried out on 39 myeloid leukemia patients including de novo cases, myelodysplastic syndrome (MDS) with transformation, and chronic myelogenous leukemia (CML) in accelerated and blast crisis, in addition to 10 healthy individuals as the reference control. Results: LYL1 expression was increased at least 2 times compared to the controls. The highest expression of this transcription factor was observed in the MDS cases transformed to acute leukemia at 7.3±3.1, p=0.0011. LYL1 expression was found in 68.2%, 75%, and 77.8% of cases of acute myeloid leukemia, CML crisis, and MDS, respectively. Significant correlation of LYL1 overexpression with some subtypes of French-American-British classification was found. There was, for the first time, significant correlation between the blood count at diagnosis and LYL1 expression (p=0.023, 0.002, and 0.031 for white blood cells, hemoglobin, and platelets, respectively). The rate of complete remission was lower with very high levels of LYL1 expression and the risk of relapse increased with higher levels of LYL1 expression, suggesting an unfavorable prognosis for cases with enhanced expression. Conclusion: Overexpression of LYL1 is highly associated with acute myeloid leukemia and shows more expression in MDS with unfavorable prognosis in response to induction chemotherapy. These observations could signal a promising tool for a therapeutic target to basic helix-loop helix protein related to transcription factors, which may improve patient outcome in acute myeloid leukemia, MDS, and CML in blast crisis.
PMID: 25035669 [PubMed]
Chronic myeloid leukemia patient with co-occurrence of BCR-ABL junction and JAK2 V617F mutation.
Int J Hematol. 2014 Jan;99(1):87-90
Authors: Xu W, Chen B, Tong X
The JAK2 V617F mutation is common in patients with Philadelphia-negative chronic myeloproliferative neoplasms, but few cases of the JAK2 V617F mutation have been described in Philadelphia-positive chronic myeloid leukemia (CML) patients. Here, we report a 21-year-old female who presented with phenotype of CML in whom BCR-ABL transcript and JAK2V617F mutation co-occurred. These findings were determined through cytogenetic analysis, fluorescence in situ hybridization, and allele-specific (AS) PCR. The patient’s BCR-ABL transcript disappeared after 6 months of treatment with imatinib, while the JAK2V617F mutation remained positive. We discuss this case with reference to the current literature.
PMID: 24293258 [PubMed - indexed for MEDLINE]
Treatment with dasatinib for chronic myeloid leukemia following imatinib-induced hepatotoxicity.
Int J Hematol. 2014 Jan;99(1):91-4
Authors: Harbaum L, Marx A, Goekkurt E, Schafhausen P, Atanackovic D
Treatment with the tyrosine kinase inhibitor (TKI) imatinib for chronic myeloid leukemia in chronic phase (CML-CP) of disease may cause severe hepatotoxicity in rare cases. However, it remains unclear (1) how imatinib-induced hepatotoxicity should be treated; and (2) if and how TKI treatment can be resumed after recovery. We report a 32-year-old woman with CML-CP and histology confirmed imatinib-induced liver toxicity after 6 months of treatment. In this case, the early administration of corticosteroid therapy resulted in rapid and complete hepatic recovery, and treatment for CML-CP with the second generation TKI dasatinib was continued safely after recovery. Thus, dasatinib represents an option for maintaining therapeutic response in patients in whom continuation of imatinib is not possible due to its hepatic toxicity.
PMID: 24264834 [PubMed - indexed for MEDLINE]
Similar outcome of patients with chronic myeloid leukemia treated with imatinib in or out of clinical trials.
Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):693-9
Authors: Yilmaz M, Kantarjian H, Jabbour E, O’Brien S, Borthakur G, Verstovsek S, Garcia-Manero G, Ravandi F, Burger J, Pierce S, Quintas-Cardama A, Cortes J
INTRODUCTION: Outcomes of CML-CP patients treated in clinical trials are frequently perceived to be not representative of those treated outside of clinical trials.
PATIENTS AND METHODS: We investigated the outcomes of patients receiving imatinib outside of a clinical trial (off protocol) or in a clinical trial (on protocol) for CML-CP.
RESULTS: We identified 65 patients treated with imatinib off protocol and 71 patients treated on protocol with standard-dose imatinib. The overall complete cytogenetic response (CCyR) rate was 83% for patients treated on and off protocol. CCyR rates 12 months after initiation of imatinib were not statistically different (61% vs. 66%, respectively; P = .15). Patients treated off protocol had similar rates of overall major molecular response (72% vs. 73%) compared with the patients treated on protocol. The 5-year event-free survival rates were 84% and 86% for off and on protocol patients, respectively. There was also no significant difference in 5-year transformation free survival (94% vs. 96%) and overall survival (96% vs. 90%).
CONCLUSION: These results suggest that patients with CML treated outside of a clinical trial might have the same excellent outcome as those treated in a clinical trial provided they are followed with the same rigor.
PMID: 24060289 [PubMed - indexed for MEDLINE]
Detection of dormant chronic myeloid leukemia clones in the bone marrow of patients in complete molecular remission.
Clin Lymphoma Myeloma Leuk. 2013 Dec;13(6):681-5
Authors: Quintás-Cardama A, Grgurevic S, Rozovski U, Li P, Estrov Z, Cortes J
BACKGROUND: Several methods are available to detect MRD in patients with CML in complete molecular remission (CMR) and taking tyrosine kinase inhibitor (TKI) therapy.
MATERIALS AND METHODS: We performed clonogenic assays on mononuclear bone marrow cells from 14 patients. Of the 10 assessable samples, 6 were from patients in CMR and 4 from patients in complete cytogenetic remission but had detectable MRD using polymerase chain reaction (PCR) analysis (positive controls). At least 10 colonies per sample were microaspirated and individual colonies were subjected to PCR analysis.
RESULTS: Of the 6 patients in CMR, 5 harbored breakpoint cluster region abelson (BCR-ABL1) negative colonies but in 1 sample, 1 of the 10 colonies analyzed was positive for BCR-ABL1. Of the 4 patients with evidence of MRD in peripheral blood, 2 had negative and 2 had positive BCR-ABL1 colonies.
CONCLUSION: MRD is still detectable using clonogenic assays in some patients with CML after achieving CMR using TKI therapy, which is likely responsible for relapse on TKI discontinuation. Because of the large number of single colonies that need to be analyzed, the use of clonogenic assays in clinical practice to determine the feasibility of TKI discontinuation is not recommended.
PMID: 24060288 [PubMed - indexed for MEDLINE]
The one-two punch: combination treatment in chronic myeloid leukemia.
Crit Rev Oncol Hematol. 2013 Dec;88(3):667-79
Authors: Sweet KL, Hazlehurst LA, Pinilla-Ibarz J
Despite the success of tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML), minimal residual disease persists, requiring indefinite treatment. Accumulated evidence has shown that leukemic stem cells (LSCs) in the bone marrow can survive TKI treatment via downstream BCR-ABL1-independent signaling pathways that are activated by soluble growth factors and interactions with the extracellular matrix in the bone marrow microenvironment. Research efforts have therefore turned to the identification and development of agents that target LSCs, and together with TKIs, have the potential to eradicate CML. A number of such agents are now under clinical investigation, and others are soon to enter early-phase studies. This review examines the pathways, molecular targets, and potential new therapeutics that, with TKIs, may provide an effective “one-two punch” to cure CML.
PMID: 23969231 [PubMed - indexed for MEDLINE]
Use of tyrosine kinase inhibitors in a patient with Brugada syndrome and chronic myeloid leukemia.
Int J Hematol. 2013 Oct;98(4):483-6
Authors: Sgherza N, Russo Rossi AV, Colonna P, Carluccio P, Delia M, Specchia G
The treatment and prognosis of chronic myeloid leukemia have dramatically changed since the introduction of tyrosine kinase inhibitors, but although several clinical trials have examined their safety with respect to heart function, no data are yet available about the use of these drugs in patients with Brugada syndrome. We report a case of Brugada syndrome diagnosed during tyrosine kinase inhibitor therapy in a 69-year-old Caucasian male with meningioma and chronic myeloid leukemia. This case report highlights the importance of an integrated approach among hematologists and cardiologists to ensure appropriate treatment with tyrosine kinase inhibitors in patients affected by chronic myeloid leukemia who also suffer from Brugada syndrome.
PMID: 23881644 [PubMed - indexed for MEDLINE]
Stem cell maintenance and disease progression in chronic myeloid leukemia.
Int J Hematol. 2013 Dec;98(6):641-7
Authors: Ito T
Chronic myeloid leukemia (CML) is a cancer of blood cells driven by the BCR-ABL1 oncogenic protein tyrosine kinase, which is the product of a reciprocal chromosomal translocation known as the Philadelphia chromosome. Discovery of tyrosine kinase inhibitors targeting the BCR-ABL1 kinase revolutionized CML therapy, but these drugs are unable to eradicate the disease due to the presence of a drug-insensitive stem cell population that sustains continued growth of the malignant cells. Resistance to therapies also increases the risk of relapse and disease progression to a more advanced phase. This review discusses emerging issues in CML research, and describes recent progress in elucidating the mechanisms of CML stem cell maintenance and disease progression.
PMID: 23550022 [PubMed - indexed for MEDLINE]
Bosutinib: a novel src/abl kinase inhibitor for chronic myelogenous leukemia.
J Adv Pract Oncol. 2013 Nov;4(6):451-5
Authors: Steinbach A, Clark SM, Clemmons AB
PMID: 25032026 [PubMed]