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Chronic Myeloid Leukemia (CML)

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Latest Research Publications

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Information for Health Professionals / Researchers (8 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Millett R, Aggarwal A, Tabbara I, Nassereddine S
Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.
Anticancer Res. 2019; 39(8):4333-4335 [PubMed] Related Publications
Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.

Lei H, Tu Y, Yang L, et al.
Quinacrine Depletes BCR-ABL and Suppresses Ph-Positive Leukemia Cells.
Cancer Invest. 2019; 37(6):242-252 [PubMed] Related Publications
Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34

Massimino M, Stella S, Tirrò E, et al.
Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3
Anticancer Res. 2019; 39(7):3949-3954 [PubMed] Related Publications
We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.

Tirrò E, Massimino M, Stella S, et al.
Efficacy of Nilotinib in a CML Patient Expressing the Three-way Complex Variant Translocation t(2;9;22).
Anticancer Res. 2019; 39(7):3893-3899 [PubMed] Related Publications
BACKGROUND/AIM: Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or second-generation tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients.
CASE REPORT: We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib.
CONCLUSION: CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.

Dereń-Wagemann IE, Kuliczkowski K
Significance of apoptosis and autophagy of leukemic blasts for the outcomes of acute myeloid leukemia patients.
Adv Clin Exp Med. 2019; 28(7):861-869 [PubMed] Related Publications
BACKGROUND: Cytostatic treatment induces apoptosis or other types of cell death like autophagy, necrosis, mitotic catastrophe, etc. Autophagy can play a role in the drug resistance of neoplastic cells, allowing the survival of blast cells under stressful conditions, such as the use of cytostatics. Studies on apoptosis and autophagy 12-24 h after the start of treatment have not been conducted until now.
OBJECTIVES: The study aimed to investigate the predictive and prognostic significance of autophagy and apoptosis in patients with acute myeloid leukemia (AML).
MATERIAL AND METHODS: The study included 38 patients. Blood was collected before and 12-24 h after the start of treatment, since at that time point, the appropriate blast cell count was still available. Autophagy was measured with the expression of the ATG5, MAP1L3, LC3-I, and LC3-II proteins. The percentage of mononuclear cells in early and late apoptosis was evaluated with flow cytometry, using the annexin V and propidium iodide (PI) binding assay.
RESULTS: The percentage of apoptotic blast cells before treatment was not associated with the response. However, in the remission group, the overall percentage of apoptotic cells measured 12-24 h after the start of treatment was higher than in non-remission patients, which was statistically significant. In neither group we found any difference in the level of autophagy before and 12-24 h after the start of treatment. Nevertheless, we observed an increasing tendency of the MAP1LC3 protein expression (not statistically significant) in the remission group 12-24 h after the start of treatment. Patients with a higher percentage of blast cells in apoptosis and with a higher expression of MAP1LC3 protein measured 12-24 h after the start of the therapy had longer overall survival (OS).
CONCLUSIONS: A higher percentage of apoptotic as well as autophagic blast cells measured 12-24 h after the start of the chemotherapy is an independent factor associated with better outcomes.

Berger MG, Bourgne C
Contribution of Chronic Myeloid Leukaemia (CML) as a Disease Model to Define and Study Clonal Heterogeneity.
Adv Exp Med Biol. 2019; 1139:171-185 [PubMed] Related Publications
Although tumour cell intra-clonal heterogeneity has been known for many years, its application in the oncology clinical practice (patient management, prognosis, etc.) remains limited. For this, chronic myeloid leukaemia (CML) is a remarkable model. Basic research studies revealed the heterogeneity of the initial clone, and led to the hypothesis of the existence of leukemic stem cells. Nevertheless, the indisputable evidence of the intra-clonal heterogeneity role in the therapeutic response came from the outcomes of the treatment with tyrosine kinase inhibitors (the first targeted therapy in medicine) combined with the early and rigorous clinical and molecular monitoring of these patients. CML management already takes this heterogeneity into account for personalized patient follow-up. The adventure continues with the objectives of better tailoring the treatment and of curing the disease in most of the patients.

Jyotsana N, Sharma A, Chaturvedi A, et al.
Lipid nanoparticle-mediated siRNA delivery for safe targeting of human CML in vivo.
Ann Hematol. 2019; 98(8):1905-1918 [PubMed] Related Publications
Efficient and safe delivery of siRNA in vivo is the biggest roadblock to clinical translation of RNA interference (RNAi)-based therapeutics. To date, lipid nanoparticles (LNPs) have shown efficient delivery of siRNA to the liver; however, delivery to other organs, especially hematopoietic tissues still remains a challenge. We developed DLin-MC3-DMA lipid-based LNP-siRNA formulations for systemic delivery against a driver oncogene to target human chronic myeloid leukemia (CML) cells in vivo. A microfluidic mixing technology was used to obtain reproducible ionizable cationic LNPs loaded with siRNA molecules targeting the BCR-ABL fusion oncogene found in CML. We show a highly efficient and non-toxic delivery of siRNA in vitro and in vivo with nearly 100% uptake of LNP-siRNA formulations in bone marrow of a leukemic model. By targeting the BCR-ABL fusion oncogene, we show a reduction of leukemic burden in our myeloid leukemia mouse model and demonstrate reduced disease burden in mice treated with LNP-BCR-ABL siRNA as compared with LNP-CTRL siRNA. Our study provides proof-of-principle that fusion oncogene specific RNAi therapeutics can be exploited against leukemic cells and promise novel treatment options for leukemia patients.

Ren X, Qin Y, Huang X, et al.
Assessment of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase receiving tyrosine kinase inhibitors.
Ann Hematol. 2019; 98(7):1627-1640 [PubMed] Related Publications
We aimed to evaluate the incidence of chronic renal injury in patients with chronic myeloid leukemia in the chronic phase (CML-CP) receiving tyrosine kinase inhibitors (TKIs) and to identify the associated factors. Data for CML-CP patients with normal estimated glomerular filtration rate (eGFR) at baseline and receiving TKI therapy ≥ 3 months were retrospectively reviewed. The CRAE (chronic renal adverse event, defined as a 30% eGFR reduction from baseline or eGFR < 60 ml/min/1.73 m

Molica M, Colafigli G, Scalzulli E, et al.
Ten-year outcome of chronic-phase chronic myeloid leukemia patients treated with imatinib in real life.
Ann Hematol. 2019; 98(8):1891-1904 [PubMed] Related Publications
Imatinib, the first BCR/ABL kinase inhibitor approved for the treatment of chronic myeloid leukemia (CML), has changed the long-term outcome of patients affected by this disease. The aim of our analysis was to report, after a median follow-up of 10.2 years (range 5.8-14.8), the long-term outcome, efficacy, and safety of imatinib treatment (frontline and after interferon failure) in a single institution cohort of 459 patients with CML in chronic phase treated outside of clinical trials. The 10-year overall survival of the whole cohort was 77.1%, while the 10-year probability of dying due to CML and other causes was 7.8% and 16%, respectively. The prognostic value of the BCR-ABL1 ratio at 3 months (⩽ 10%) and of complete cytogenetic response and major molecular response at 1 year was confirmed also in the real-life practice. The EUTOS long-term survival score better stratified the baseline risk of dying of CML compared with other risk scores. Two hundred thirty-six (51.4%) patients achieved a deep molecular response during imatinib treatment after a median time of 4.57 years, and 95 (20.6%) had a stable deep molecular response maintained for at least 2 consecutive years. Imatinib was associated with a low rate of serious cardiovascular events and second neoplasia. This 10-year real-life follow-up study shows that imatinib maintains efficacy over time and that long-term administration of imatinib is not associated with notable cumulative or late toxic effects.

Xu J, Wu M, Zhu S, et al.
Detecting the stable point of therapeutic effect of chronic myeloid leukemia based on dynamic network biomarkers.
BMC Bioinformatics. 2019; 20(Suppl 7):202 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Most researches of chronic myeloid leukemia (CML) are currently focused on the treatment methods, while there are relatively few researches on the progress of patients' condition after drug treatment. Traditional biomarkers of disease can only distinguish normal state from disease state, and cannot recognize the pre-stable state after drug treatment.
RESULTS: A therapeutic effect recognition strategy based on dynamic network biomarkers (DNB) is provided for CML patients' gene expression data. With the DNB criteria, the DNB with 250 genes is selected and the therapeutic effect index (TEI) is constructed for the detection of individual disease. The pre-stable state before the disease condition becomes stable is 1 month. Through functional analysis for the DNB, some genes are confirmed as key genes to affect the progress of CML patients' condition.
CONCLUSIONS: The results provide a certain theoretical direction and theoretical basis for medical personnel in the treatment of CML patients, and find new therapeutic targets in the future. The biomarkers of CML can help patients to be treated promptly and minimize drug resistance, treatment failure and relapse, which reduce the mortality of CML significantly.

Chen SH, Chow JM, Hsieh YY, et al.
HDAC1,2 Knock-Out and HDACi Induced Cell Apoptosis in Imatinib-Resistant K562 Cells.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
Since imatinib (Glivec or Gleevec) has been used to target the BCR-ABL fusion protein, chronic myeloid leukemia (CML) has become a manageable chronic disease with long-term survival. However, 15%-20% of CML patients ultimately develop resistance to imatinib and then progress to an accelerated phase and eventually to a blast crisis, limiting treatment options and resulting in a poor survival rate. Thus, we investigated whether histone deacetylase inhibitors (HDACis) could be used as a potential anticancer therapy for imatinib-resistant CML (IR-CML) patients. By applying a noninvasive apoptosis detection sensor (NIADS), we found that panobinostat significantly enhanced cell apoptosis in K562 cells. A further investigation showed that panobinostat induced apoptosis in both K562 and imatinib-resistant K562 (IR-K562) cells mainly via H3 and H4 histone acetylation, whereas panobinostat targeted cancer stem cells (CSCs) in IR-K562 cells. Using CRISPR/Cas9 genomic editing, we found that HDAC1 and HDAC2 knockout cells significantly induced cell apoptosis, indicating that the regulation of HDAC1 and HDAC2 is extremely important in maintaining K562 cell survival. All information in this study indicates that regulating HDAC activity provides therapeutic benefits against CML and IR-CML in the clinic.

Stella S, Zammit V, Vitale SR, et al.
Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib.
Int J Mol Sci. 2019; 20(9) [PubMed] Free Access to Full Article Related Publications
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Sheng Y, Ji Z, Zhao H, et al.
Downregulation of the histone methyltransferase SETD2 promotes imatinib resistance in chronic myeloid leukaemia cells.
Cell Prolif. 2019; 52(4):e12611 [PubMed] Related Publications
OBJECTIVES: Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain-containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR-ABL remain unclear.
MATERIALS AND METHODS: The level of SETD2 in imatinib-sensitive and imatinib-resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real-time PCR. We analysed CD34
RESULTS: SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB-04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect.
CONCLUSIONS: Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

Luo N, Xia Q, Zhang L, et al.
One-step discrimination of BCR/ABL
Anal Chim Acta. 2019; 1067:129-136 [PubMed] Related Publications

Caocci G, Mulas O, Abruzzese E, et al.
Incidence and evaluation of predisposition to cardiovascular toxicity in chronic myeloid leukemia patients treated with bosutinib in the real-life practice.
Ann Hematol. 2019; 98(8):1885-1890 [PubMed] Related Publications
There is little information about cardiovascular adverse event (CV-AE) incidence in chronic myeloid leukemia (CML) patients treated with bosutinib in the real-life practice. We identified 54 consecutive CML patients treated with bosutinib, stratified according to the Systematic Coronary Risk Evaluation (SCORE) assessment, based on sex, age, smoking habits, systolic blood pressure, and total cholesterol levels. The 40-month cumulative incidence of CV-AEs was 25.2 ± 8.1%. Patients with the SCORE of high-very high showed a significantly higher incidence of CV-AEs (55 ± 12.9% vs 9 ± 9.5%; p = 0.002). Overall, 9 CV-AEs were reported, with 2 deaths attributed to CV-AE. In conclusion, the SCORE assessment before starting treatment is helpful in identifying CV-AE high-risk patients during bosutinib treatment.

Kizilors A, Crisà E, Lea N, et al.
Effect of low-level BCR-ABL1 kinase domain mutations identified by next-generation sequencing in patients with chronic myeloid leukaemia: a population-based study.
Lancet Haematol. 2019; 6(5):e276-e284 [PubMed] Related Publications
BACKGROUND: Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. Next-generation sequencing (NGS) allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated. We aimed to examine the clinical effects of low-level kinase domain mutations identified using NGS in patients with chronic myeloid leukaemia.
METHODS: In this population-based study, we included consecutive patients newly diagnosed with chronic myeloid leukaemia treated with first-line tyrosine kinase inhibitors, and patients identified at the time of resistance to first-line treatment with imatinib at six institutions (teaching hospitals and district hospitals) in southeast England. We screened patients for BCR-ABL1 kinase domain mutations using NGS, irrespective of patient response to tyrosine kinase inhibitor therapy. When we detected a mutation with NGS, we retrospectively analysed all previous samples to establish the date of first occurrence and subsequent kinetics of the mutant subclone (or subclones). The primary endpoints of this study were progression-free and event-free survival at 5 years.
FINDINGS: Between Feb 1, 2007, and Dec 31, 2014, we screened 121 patients with chronic myeloid leukaemia for BCR-ABL1 kinase domain mutation. 99 consecutive patients were newly diagnosed, with available sequential RNA stored. The remaining 22 patients were diagnosed between June 1, 1999, and June 30, 2006, and were screened at the time of resistance to first-line treatment with imatinib. Imatinib was the first-line treatment for 111 patients, nilotinib for seven patients, and dasatinib for three patients. We detected a kinase domain mutation in 25 (21%) of 121 patients. Low-level kinase domain mutations were first identified in 17 (68%) of 25 patients with mutation. For patients with a complete cytogenetic response, 13 (14%) of 93 patients screened had a mutation. Five (71%) of the seven patients with a clinically relevant mutation lost complete cytogenetic response compared with 15 (17%) of 86 patients without a clinically relevant mutation (80 patients without mutation and six patients with a tyrosine kinase inhibitor-sensitive mutation, p=0·0031). Patients harbouring a mutant clone had poorer 5-year progression-free survival (65·3% [95% CI 40·5-81·8] vs 86·9% [75·8-93·2]; p=0·0161) and poorer 5-year event-free survival (22·2% [CI 5·6-45·9] vs 62·0% [50·4-71·6]; p<0·0001) than did patients without a mutation. We identified a kinase domain mutation in four (10%) of 41 patients with samples available at 3 months after starting first-line tyrosine kinase inhibitor treatment; all four subsequently progressed to accelerated phase disease compared with only three (8%) of 37 without a mutation (p<0·0001).
INTERPRETATION: NGS reliably and consistently detected early appearance of kinase domain mutations that would not otherwise be detected by Sanger sequencing. For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications. NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care.

Palejwala AH, O'Connor KP, Shi H, et al.
Chronic myeloid leukemia manifested as myeloid sarcoma: Review of literature and case report.
J Clin Neurosci. 2019; 64:269-276 [PubMed] Related Publications
In this report, we present the case of a 50-year-old woman presenting with an intraparenchymal myeloid sarcoma manifesting as weakness. She has a history of chronic myeloid leukemia (CML) treated with imatinib not taken consistently with a relapse to blast crisis, and then an isolated relapse as a myeloid sarcoma manifesting as facial and extremity weakness. An MRI of the brain showed an enhancing, well-circumscribed mass within the frontal lobe with edema extending to the motor strip. Based on tumor size, focality, location, growth rate, and patient's symptoms, surgeons determined that the patient should undergo surgical resection. Postoperatively, the patient had full resolution of her acute neurological symptoms without post-operative complications. Post-operative MRI showed minimal enhancement suggesting post-surgical changes vs minimal residual tumor. The patient was scheduled to undergo whole brain radiotherapy with supplemental direct radiation to the site of resection. This is the first report of safe and complete resection of an intraparenchymal myeloid sarcoma. It is meant to inform neurosurgeons that brain tumors can be potentially CML-related; additionally, we review CML's manifestations in the central nervous system and how neurosurgeons can consider optimal management given as there are no guidelines on how to treat CML-related CNS disease.

Smeding C, Szydło A, Pieluszczak K, et al.
Efficacy and Safety of Imatinib in Paediatric CML - A Single Centre Study.
In Vivo. 2019 May-Jun; 33(3):869-875 [PubMed] Free Access to Full Article Related Publications
BACKGROUND/AIM: Chronic myeloid leukaemia (CML) rarely affects the paediatric population and has an incidence of 0.06-0.12/100,000 children per year. The dire clinical course of paediatric CML is further exacerbated by the adverse effects of long-term imatinib therapy.
PATIENTS AND METHODS: Our cohort comprised 14 CML patients who were treated with imatinib between July 2010 and September 2018. The European Leukaemia Net (ELN) standard milestones of response criteria were used to evaluate its therapeutic effectiveness.
RESULTS: Complete haematological remission and partial cytogenetic response were achieved in all patients. Complete cytogenetic response was achieved in seven patients. Major molecular response was achieved in six patients. Two patients underwent haematopoietic stem cell transplantation due to unsatisfactory response to imatinib.
CONCLUSION: Imatinib is effective in treating paediatric CML and limits the progression to advanced stages, however, the quality of life still needs to be optimised.

Shen N, You Y, Zhong ZD, et al.
Monitoring and Analysis of Chinese Chronic Myeloid Leukemia Patients Who Have Stopped Tyrosine Kinase Inhibitor Therapy.
Curr Med Sci. 2019; 39(2):211-216 [PubMed] Related Publications
Discontinuation of tyrosine kinase inhibitor (TKI) therapy after achieving a persistent deep molecular response (DMR) is an urgently needed treatment goal for chronic myeloid leukemia (CML) patients and has been included in the National Comprehensive Cancer Network (NCCN) guidelines (version 2.2017) for CML. Indeed, various studies have confirmed the feasibility of discontinuing TKI therapy. In this study, we analyzed data from 45 CML patients who had discontinued TKI therapy. Univariate analysis was performed to predict factors that were potentially related to treatment-free remission (TFR) and identify the differences between early relapse and late relapse. Out of the 45 patients, 20 exhibited molecular relapse after a median follow-up of 18 months (range, 1-54 months), and the estimated TFR at 24 months was 40%. The univariate analysis revealed that a high Sokal score and interruptions or dose reductions during TKI treatment were the only baseline factors associated with poor outcomes. Our results indicate that TKI discontinuation could be successfully put into practice in China.

Vatanmakanian M, Tavallaie M, Ghadami S
Imatinib independent aberrant methylation of NOV/CCN3 in chronic myelogenous leukemia patients: a mechanism upstream of BCR-ABL1 function?
Cell Commun Signal. 2019; 17(1):38 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The NOV gene product, CCN3, has been reported in a diverse range of tumors to serve as a negative growth regulator, while acting as a tumor suppressor in Chronic Myelogenous Leukemia (CML). However, the precise mechanism of its silencing in CML is poorly understood. In the current study, we aimed to query if the gene regulation of CCN3 is mediated by the promoter methylation in the patients with CML. In addition, to clarify whether the epigenetic silencing is affected by BCR-ABL1 inhibition, we assessed the methylation status in the patients at different time intervals following the tyrosine kinase inhibition using imatinib therapy, as the first-line treatment for this type of leukemia.
METHODS: To address this issue, we applied bisulfite-sequencing technique as a high-resolution method to study the regulatory segment of the CCN3 gene. The results were analyzed in newly diagnosed CML patients as well as following imatinib therapy. We also evaluated the correlation of CCN3 promoter methylation with BCR-ABL1 levels.
RESULTS: Our findings revealed that the methylation occurs frequently in the promoter region of CML patients showing a significant increase of the methylated percentage at the CpG sites compared to normal individuals. Interestingly, this hypermethylation was indicated to be independent of BCR-ABL1 titers in both groups, which might suggest a mechanism beyond the BCR-ABL1 function.
CONCLUSION: Despite suggesting that the CCN3 hypermethylation acts as a molecular mechanism independent of BCR-ABL1 function in CML patients, this scenario requires further validation by complementary experiments. In the case of acting upstream of BCR-ABL1 signaling, the methylation marker can provide early detection and a novel platform for targeted epigenetic modifiers for efficient treatment in imatinib resistant patients.

Cortes JE, Gambacorti-Passerini C, Deininger MW, et al.
Patient-reported outcomes in the phase 3 BFORE trial of bosutinib versus imatinib for newly diagnosed chronic phase chronic myeloid leukemia.
J Cancer Res Clin Oncol. 2019; 145(6):1589-1599 [PubMed] Related Publications
BACKGROUND: In the phase 3 BFORE trial (NCT02130557), treatment with bosutinib resulted in a significantly higher major molecular response rate at 12 months versus imatinib in the modified intent-to-treat (mITT) population of patients with newly diagnosed chronic phase chronic myeloid leukemia (CP CML). Assessment of patient-reported outcomes (PROs) was an exploratory objective.
METHODS: Patients with newly diagnosed CP CML were randomized 1:1 to receive once-daily bosutinib 400 mg or imatinib 400 mg as first-line therapy. Patients completed the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu) and EuroQoL-5 Dimensions (EQ-5D) questionnaires at baseline, every 3 months for the first 24 months of treatment, every 6 months thereafter, and at treatment completion. We report PRO results at month 12 in the mITT population (bosutinib: n = 246; imatinib: n = 241).
RESULTS: Mean FACT-Leu combined and subscale scores were similar at baseline in the bosutinib and imatinib arms; at month 12, all scores demonstrated improvement or maintenance of health-related quality of life (HRQoL) in both treatment arms. Repeated-measures mixed-effects models showed no significant difference between bosutinib and imatinib for any FACT-Leu score. Functional health status, as measured by EQ-5D, also demonstrated improvement or maintenance with bosutinib and imatinib at month 12.
CONCLUSIONS: Similar improvements in PROs compared with baseline were seen after 12 months of treatment with first-line bosutinib or imatinib in the BFORE trial. Newly diagnosed patients with CP CML receiving bosutinib or imatinib can preserve or improve HRQoL during treatment, although clinical efficacy was superior with bosutinib.

Wang R, Cong Y, Li C, et al.
Predictive value of early molecular response for deep molecular response in chronic phase of chronic myeloid leukemia.
Medicine (Baltimore). 2019; 98(15):e15222 [PubMed] Free Access to Full Article Related Publications
To investigate the association of 3- and 6-month BCR-ABL transcript levels on the international scale (BCR-ABL) and other factors with deep molecular response (DMR) achievement in chronic myeloid leukemia (CML)-chronic phase (CP) patients receiving tyrosine kinase inhibitor (TKI) therapy.We retrospectively analyzed the clinical data of 206 patients enrolled in our hospital between January 2010 and July 2018. These patients were initially diagnosed with CML-CP and received imatinib or nilotinib therapy. Early molecular response (EMR) was assessed based on BCR-ABL (IS: on the international scale) transcript level at 3 and 6 months. Potential factors impacting DMR achievement were identified using Cox proportional hazard regression models. The effects of EMR achievement on the cumulative incidence of MR4.0 were investigated via Kaplan-Meier analysis.Multivariate Cox regression analysis showed that a BCR-ABL transcript level at 3 and 6 months of TKI therapy was an independent factor for the achievement of MR4.0, which was nevertheless not related to age, gender, Sokal score, hemoglobin level, or white blood cell (WBC) count at the initial time of diagnosis. Patients achieving an EMR (EMR: 3-month BCR-ABL ≤10%, 6-month BCR-ABL <1%) were more likely to reach MR4.0 than patients failing to achieve EMR (P1 <.001, P2 <.001). Patients who had 3-month BCR-ABL ≤1% were more likely to reach MR4.0 than those who had 3-month BCR-ABL of 1% to 10% or >10% (P1 = .001, P2 <.001). Similarly, patients who had 6-month BCR-ABL ≤0.1% were more likely to achieve MR4.0 than those in the 0.1% to 1% and ≥1% groups (P1 <.001, P2 <.001). Also, a higher percentage of patients on nilotinib therapy achieved EMR compared with patients on imatinib therapy (93.3% vs 63.6% on 3-month nilotinib therapy, P = .001; 88.9% vs 59.9% on 6-month nilotinib therapy, P = .004).This study demonstrates that EMR, especially a 3-month BCR-ABL ≤1% and 6-month BCR-ABL ≤0.1%, have predictive value for DMR achievement. In addition, there is a higher percentage of patients receiving nilotinib therapy achieved EMR than that of those receiving imatinib therapy.

Sazawal S, Chhikara S, Singh K, et al.
Distribution of common BCR-ABL fusion transcripts and their impact on treatment response in Imatinib treated CML patients: A study from India.
Indian J Pathol Microbiol. 2019 Apr-Jun; 62(2):256-260 [PubMed] Related Publications
Background: Philadelphia chromosome (Ph): Hallmark of CML is caused by reciprocal translocation between chromosomes 9 and 22 resulting in BCR-ABL fusion protein. Most commonly associated breakpoint with CML is M-bcr in exon 13 or exon 14, producing splice variant b2a2 or b3a2 respectively. The distribution of these transcripts and their influence on clinico-hematological parameters is variable. Impact of the fusion transcripts on treatment outcome in Imatinib treated CML patients is still a matter of debate.
Aims/settings and design: We conducted this study on 400 CML-CP patients to look for the distribution of fusion transcripts i.e. b3a2 and b2a2, their clinico-hematological profile and impact on treatment response in patients treated with Imatinib.
Material and Methods: CML-CP was diagnosed by reverse transcriptase PCR (RT-PCR) for the BCR-ABL fusion transcript. Real-time quantitative PCR (RQ-PCR) was performed on peripheral blood every 3-6 monthly to look for treatment response.
Results: The overall frequency of b3a2 transcript was observed in 288 (72%) followed by b2a2 in 104 (26%) and hybrid fusion transcript (b3a2 + b2a2) was seen in 8 (2%) cases. MMR was attained in 198/288 (68.7%) patients with b3a2 transcript and 90/288 (31.3%) patients failed to achieve MMR after 12 months of Imatinib therapy. Among the patients with b2a2 transcript, 44/104 (42.3%) patients achieved MMR and 60/104 (57.7%) patients failed to achieve MMR after 12 months of Imatinib therapy.
Conclusions: In conclusion, the frequency of b3a2 transcript was more as compared to b2a2 transcript. MMR was significantly higher in patients with b3a2 transcript as compared to patients with b2a2.

Wang X, Yang J, Guo G, et al.
Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.
Mol Cancer. 2019; 18(1):84 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Möbius S, Schenk T, Himsel D, et al.
Results of the European survey on the assessment of deep molecular response in chronic phase CML patients during tyrosine kinase inhibitor therapy (EUREKA registry).
J Cancer Res Clin Oncol. 2019; 145(6):1645-1650 [PubMed] Related Publications
PURPOSE: The advent of tyrosine kinase inhibitor (TKI) therapies has revolutionized the treatment of chronic myeloid leukemia (CML). The European LeukemiaNet (ELN) recommends quantification of BCR-ABL1 transcripts by real-time quantitative PCR every 3 months during TKI treatment. Since a proportion of patients in deep molecular response (DMR: MR
METHODS: Data were collected on the standardized assessment of molecular response in the context of real-life practice. BCR-ABL1 transcript levels after > 2 years of TKI therapy were evaluated for DMR by local laboratories as well as standardized EUTOS laboratories. Since standardized molecular monitoring is a prerequisite for treatment discontinuation, central surveillance of the performance of the participating laboratories was carried out.
RESULTS: Between 2014 and 2017, 3377 peripheral blood samples from 1117 CML patients were shipped to 11 standardized reference laboratories in six European countries. BCR-ABL1 transcript types were b3a2 (41.63%), b2a2 (29.99%), b2a2/b3a2 (3.58%) and atypical (0.54%). For 23.72% of the patients, the initial transcript type had not been reported. Response levels (EUTOS laboratory) were: no MMR, n = 197 (6.51%); MMR, n = 496 (16.40%); MR
CONCLUSIONS: Multicenter DMR assessment is feasible in the context of real-life clinical practice in Europe. Information on the BCR-ABL1 transcript type at diagnosis is crucial to accurately monitor patients' molecular response during or after TKI therapy.

Cai H, Li L, Jiang J, et al.
Costunolide enhances sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin through PI3K/Akt pathway.
Phytother Res. 2019; 33(6):1683-1688 [PubMed] Related Publications
Costunolide, a sesquiterpene lactone, a small molecular monomer extracted from Inula helenium, has been reported to possess antiproliferative effects on several cancer cell lines. The current study was designed to evaluate the effect of costunolide on sensitivity of K562/ADR chronic myeloid leukemia cells to doxorubicin. The antiproliferative effect of costunolide was assessed by CCK-8 assay. Flow cytometry and Western blot were used to examine the mechanisms of antileukemia action. Costunolide dramatically enhanced doxorubicin-induced antiproliferative activity against K562/ADR cells through inhibition of PI3K/Akt pathway, activation of caspases 3, cleavage of poly (ADP-ribose) polymerase, and downregulation of p-glycoprotein expression. These results demonstrate that costunolide may be a potent therapeutic agent against CML.

Hassan FM
OGG1 rs1052133 Polymorphism and Genetic Susceptibility to Chronic Myelogenous Leukaemia
Asian Pac J Cancer Prev. 2019; 20(3):925-928 [PubMed] Related Publications
Background: In some cancer cells, the OGG1 gene is somatically mutated and highly populated. This study was conducted to examine whether OGG1 rs1052133 polymorphism is associated with the genetic background of chronic myelogenous leukaemia (CML) in Sudan. Methods: A total of 332 CML patients and 70 healthy controls were included in this study. Overall, the genotypes (P=0.0000) and allele (C vs. G, P=0.0007) differed considerably in the frequencies of OGG1 rs1052133 polymorphism between CML patients and controls. Our study is the first to evaluate the association of polymorphism with CML risk with OGG1 rs1052133. Results: A statistically significant association was observed between the genotype distribution of OGG1 rs1052133 polymorphism and CML (P=0.0000) patients. A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls when compared OGG1 rs1052133 genotypes with CML stages. Results: Genotype and allele frequencies of OGG1 rs1052133 among CML patients. A statistically significant association was observed between the genotype distribution of the OGG1 rs1052133 polymorphism and CML patients (P=0.0000). A similar result was also observed in the allele distribution (C vs. G, P=0.0007) compared with healthy controls with stages of CML in OGG1 rs1052133 genotypes. Conclusion: The results suggest that single nucleotide polymorphism in the gene involved in the restoration of DNA base excision (OGG1 rs1052133) can play a key role in the risk of appearance of CML. To clarify the role of OGG1 in the genetic basis of CML, further case control with larger sample sizes and fine-mapping is required.

Lee HR, Baek KH
Role of natural killer cells for immunotherapy in chronic myeloid leukemia (Review).
Oncol Rep. 2019; 41(5):2625-2635 [PubMed] Related Publications
The majority of natural killer (NK) cells serve an important role in eliminating malignant cells. The cytotoxic effects of NK cells were first identified against leukemia cells, and it is now hypothesized that they may have a critical role in leukemia therapy. The cellular functions of NK cells are mediated by their cell surface receptors, which recognize ligands on cancer cells. The role of NK cells is specifically regulated by the activating or inhibitory killer cell immunoglobulin‑like receptors (KIRs) on their surface, which bind to the human leukocyte antigen (HLA) class I ligands present on the target cells. The association between KIR and HLA is derived from the diversity of KIR/HLA gene profiles present in different individuals, and this determines the cytotoxic effect of NK cells on cancer cells. Chronic myeloid leukemia (CML) is a hematological leukemia characterized by the hyper‑proliferation of myeloid cells, with the majority of patients with CML presenting with abnormal immune cells. Tyrosine kinase inhibitors are the present standard therapy for CML, but are associated with numerous adverse side effects. Various studies have proposed CML therapy by immunotherapeutic approaches targeting the immune cells. This review summarizes the contents of NK cells and the association between KIR/HLA and leukemia, especially CML. This is followed by a discussion on the development of NK cell immunotherapy in hematological malignancies and research into strategies to enhance NK cell function for CML treatment.

Jia X, Zheng Y, Guo Y, Chen K
Sodium butyrate and panobinostat induce apoptosis of chronic myeloid leukemia cells via multiple pathways.
Mol Genet Genomic Med. 2019; 7(5):e613 [PubMed] Free Access to Full Article Related Publications
PURPOSE: Histone deacetylase inhibitor (HDACI) is a novel therapeutic option for cancer. However, the effects of HDACIs on chronic myeloid leukemia (CML) and the underlying mechanisms are still unknown. The aim of this study was to investigate the effect and the mechanism-of-action of two HDACI members, sodium butyrate (NaBu) and panobinostat (LBH589) in K562 and the adriamycin-resistant cell line K562/ADR.
METHODS: Cell viability was assessed using MTT assay. Cell apoptosis was detected with flow cytometry. Cell cycle analysis and western blot were performed to explore the possible molecules related to HDACIs effects.
RESULTS: The effect of NaBu was more powerful on K562/ADR than on K562 cells. LBH589 triggered apoptosis and inhibited the growth of K562 cells. Both HDACIs inhibited K562 and K562/ADR cells via activation of intrinsic/extrinsic apoptotic pathways and inhibition of AKT-mTOR pathway while NaBu also activated endoplasmic reticulum stress (ERS) mediated apoptotic pathway in K562/ADR cells. LBH589 reduced the expression of drug-resistant related proteins in K562 cells. However, neither NaBu nor LBH589 could significantly influence the expression of the drug-resistant related proteins in K562/ADR cells.
CONCLUSION: The combination of HDACI and other therapeutic strategies are likely required to overcome drug resistance in CML therapy.

Wang W, Niu S, Qiao L, et al.
Usnea Acid as Multidrug Resistance (MDR) Reversing Agent against Human Chronic Myelogenous Leukemia K562/ADR Cells via an ROS Dependent Apoptosis.
Biomed Res Int. 2019; 2019:8727935 [PubMed] Free Access to Full Article Related Publications
Purpose: Multidrug resistance (MDR) is a major obstacle in chemotherapy of leukemia treatments. In this paper, we investigated Usnea Acid (UA) as MDR reversal agent on hematologic K562/ADR cells via ROS dependent apoptosis.
Methods: CCK8 assay was used to measure cell viability rate of K562/ADR. Intracellular reactive oxygen species (ROS) generation, cell cycle distribution, cell apoptosis were measured with flow cytometry, respectively. Proteins related to apoptosis were measured by Western blot. Intracellular Adriamycin accumulation was observed by confocal microscopy and measured by flow cytometry.
Results: In vitro study showed intracellular Adriamycin accumulation was remarkably increased by UA. Cell viability treated with Adr (4
Conclusion: These data provide compelling evidence that UA is a promising agent against MDR in leukemia cell line and suggest a promising therapeutic approach for leukemia.

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