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Chronic Myeloid Leukemia (CML)

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Latest Research Publications

Information Patients and the Public (17 links)

Information for Health Professionals / Researchers (8 links)

Latest Research Publications

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

Vonka V, Petráčková M, Humlová Z, et al.
The Relationship of Kynurenine and Neopterin Levels and Their Association with a Selection of Other Immune Markers in Chronic Myeloid Leukaemia Patients.
Folia Biol (Praha). 2016; 62(6):235-240 [PubMed] Related Publications
Among malignant diseases, chronic myeloid leukaemia (CML) is one of the best suited candidates for immunotherapy. For this purpose it is necessary to broaden the present knowledge on the immunology of this disease. As a part of such a project, the levels of kynurenine (KYN) and neopterin (NPT) were studied in 28 CML patients and in the same number of healthy subjects. At diagnosis, both KYN and NPT levels were found to be elevated in a significant portion of the patients and dependent on their leukocyte count. As in the case of KYN, increased NPT levels dropped after achieving remission. When correlating KYN and NPT levels with a selection of other markers tested, significant association was revealed only in the case of CRP and IL-6. However, there were several patients with increased KYN levels in whom NPT was not detected, and vice versa. The relapse of the disease observed in two patients was accompanied by an increased level of NPT in both cases, but by an increased level of KYN in only one of them. No significant correlation was found between KYN and NPT levels in sera taken at diagnosis. However, when the whole set of sera was taken into consideration, the association became statistically significant. Although the data obtained revealed a number of similarities between KYN and NPT production in CML patients, it also suggested a difference in the kinetics of these two biomarkers' production.

Lu Y, Li Y, Chai X, et al.
Long noncoding RNA HULC promotes cell proliferation by regulating PI3K/AKT signaling pathway in chronic myeloid leukemia.
Gene. 2017; 607:41-46 [PubMed] Related Publications
Aberrant expression of long noncoding RNA (lncRNA) HULC is associated with various human cancers. However, the role of HULC in chronic myeloid leukemia (CML) is unknown. In this study, we found that HULC was remarkably overexpressed in both leukemia cell lines and primary hematopoietic cells derived from CML patients. The increase in HULC expression was positively correlated with clinical stages in CML. Moreover, the knockdown of HULC significantly inhibited CML cell proliferation and induced apoptosis by repressing c-Myc and Bcl-2. Furthermore, inhibition of HULC enhanced imatinib-induced apoptosis of CML cells. Further experiments demonstrated that HULC silencing markedly suppressed the phosphorylation of PI3K and AKT, indicating that enhancement of imatinib-induced apoptosis by HULC inhibition is related with the reduction of c-Myc expression and inhibition of PI3K/Akt pathway activity. Furthermore, HULC could modulate c-Myc and Bcl-2 by miR-200a as an endogenous sponge. Taken together, these results reveal that HULC promotes oncogenesis in CML and suggest a potential strategy for the CML treatment.

Song JX, Dian ZJ, Wen Y, et al.
Assessment of the Number and Phenotype of Macrophages in the Human BMB Samples of CML.
Biomed Res Int. 2016; 2016:8086398 [PubMed] Free Access to Full Article Related Publications
Macrophages have emerged as a key player in tumor biology. However, their number and phenotype in human bone marrow of biopsy (BMB) samples of chronic myeloid leukemia (CML) and their association with disease progression from an initial chronic phase (CP) to accelerated phase (AP) to advanced blast phase (BP) are still unclear. BMB samples from 127 CML patients and 30 patients with iron-deficiency anemia (IDA) as control group were analyzed by immunohistochemistry. The expression levels of CD68, CD163, and CD206 in BMB samples of CML patients were significantly higher than those in the patients of control group (P < 0.01), and we observed that their positive expression was gradually elevated during the transformation of CML-CP to AP to BP (P < 0.01). However, the expressions of CD68, CD163, and CD206 in released group were downregulated and contrasted to these in control group; there exists statistical significance (P < 0.01). The percentage ratio of CD163 and CD206 to CD68 was pronounced to be increasing from CML-CP to AP to BP (P < 0.01). Hence, the higher proportion of CD68(+), CD163(+) and CD206(+) macrophages in BMB samples can be considered a key factor for disease progression of CML patients. Targeting macrophages, especially the M2 phenotype may help in designing therapeutic strategies for CML.

Furundarena JR, Sainz M, Uranga A, et al.
Comparison of abnormal cell flagging of the hematology analyzers Sysmex XN and Sysmex XE-5000 in oncohematologic patients.
Int J Lab Hematol. 2017; 39(1):58-67 [PubMed] Related Publications
INTRODUCTION: Hematology analyzers should optimize flagging while minimizing false-negative results and unnecessary microscopic reviews.
METHODS: We compared flagging performance of Sysmex XE-5000 and XN analyzers in oncohematologic patients. Differential counts were performed by Cellavision digital system (100 cells) and a hematologist (another 100 cells).
RESULTS: First, we included 292 samples (86 with blasts): 28 acute lymphoblastic leukemia, 88 acute myeloid leukemia, 91 myelodysplastic syndromes, 45 chronic myeloproliferative neoplasms, and 40 chronic myelomonocytic leukemia. Sensitivity, specificity and efficiency to detect blasts were 59.3%, 88.3%, and 79.8% for XE-5000 analyzer and 70.9%, 91.3%, and 85.2% for the XN analyzer. Then, we included 111 lymphoid malignancies. In 55 CLL XE-5000 flagged for Abn Lympho/L_Blasts?, XN flagged for Abn Lympho?. In one-third of 19 samples with splenic marginal lymphoma, none of the analyzers flagged. In 5 Sézary syndrome cases, XE-5000 triggered the Abn Lympho/L_Blasts? flag while the flagging in XN was less consistent: Abn Lympho? Blasts? and Atypical Lympho?. In 5 hairy cell leukemias, both analyzers only flagged one sample. In 13 myelomas, XE-5000 generated Atypical Lympho? flag; XN triggered more variable flags. In other lymphoid malignancies, flags were variable. XN analyzer generates less samples with false basophilia.
CONCLUSION: XN analyzer has improved blast detection in oncohematologic patients. Operators cannot rely on the blast flag alone but have to consider other flags and hemogram data. In lymphoproliferative disorders, XN analyzer yields less samples with pseudobasophilia. Both analyzers must improve flagging for hairy cell leukemia.

Horiguchi M, Fujioka M, Kondo T, et al.
Improved FRET Biosensor for the Measurement of BCR-ABL Activity in Chronic Myeloid Leukemia Cells.
Cell Struct Funct. 2017; 42(1):15-26 [PubMed] Related Publications
Although the co-development of companion diagnostics with molecular targeted drugs is desirable, truly efficient diagnostics are limited to diseases in which chromosomal translocations or overt mutations are clearly correlated with drug efficacy. Moreover, even for such diseases, few methods are available to predict whether drug administration is effective for each individual patient whose disease is expected to respond to the drug(s). We have previously developed a biosensor based on the principle of Förster resonance energy transfer to measure the activity of the tyrosine kinase BCR-ABL and its response to drug treatment in patient-derived chronic myeloid leukemia cells. The biosensor harbors CrkL, one of the major substrates of BCR-ABL, and is therefore named Pickles after phosphorylation indicator of CrkL en substrate. The efficacy of this technique as a clinical test has been demonstrated, but the number of cells available for analysis is limited in a case-dependent manner, owing to the cleavage of the biosensor in patient-derived leukemia cells. Here, we describe an improved biosensor with an amino acid substitution and a nuclear export signal being introduced. Of the two predicted cleavage positions in CrkL, the mutations inhibited one cleavage completely and the other cleavage partially, thus collectively increasing the number of cells available for drug evaluation. This improved version of the biosensor holds promise in the future development of companion diagnostics to predict responses to tyrosine kinase inhibitors in patients with chronic myeloid leukemia.

Yamada T, Nannya Y, Shimizu M, et al.
Symptomatic Acute Pancreatitis Induced by Nilotinib: A Report of Two Cases.
Intern Med. 2016; 55(23):3495-3497 [PubMed] Free Access to Full Article Related Publications
Nilotinib is a selective tyrosine kinase inhibitor for the treatment of Philadelphia chromosome-positive leukemias. An elevation of the pancreatic enzyme level is one of the major adverse events associated with nilotinib, but whether or not nilotinib induces symptomatic pancreatitis remains to be elucidated. The cases of two chronic myeloid leukemia patients treated with nilotinib who developed symptomatic acute pancreatitis on the third and fifth day of nilotinib administration are herein presented. Since both patients had no other etiologies for pancreatitis, nilotinib was considered to be the causal agent. The withdrawal of nilotinib resulted in a prompt recovery. These cases underline the importance of recognizing pancreatitis as a possible adverse event associated with nilotinib.

Ahmad HM, Muiwo P, Muthuswami R, Bhattacharya A
FosB regulates expression of miR-22 during PMA induced differentiation of K562 cells to megakaryocytes.
Biochimie. 2017; 133:1-6 [PubMed] Related Publications
Expression of many miRNAs is altered in different cancers and these changes are thought to play a key role in formation and progression of cancer. In chronic myelogenous leukemia (CML) a number of miRNAs are known to be down regulated as compared to normal cells. In this report we have investigated the mechanism of this down regulation by using PMA induced differentiation of CML cell line K562 to megakaryocytes as an experimental system. On treatment with PMA, expression of many down regulated miRNAs including miR-22 is induced. PMA also induces expression of several transcription factors, including FosB, EGR1 and EGR2. Our results using a number of approaches, such as promoter reporter assay, FosB knock down and Chip assay, suggest that the expression of miR-22 is regulated transcriptionally by FosB.

Xiao Y, Jiao C, Lin Y, et al.
lncRNA UCA1 Contributes to Imatinib Resistance by Acting as a ceRNA Against miR-16 in Chronic Myeloid Leukemia Cells.
DNA Cell Biol. 2017; 36(1):18-25 [PubMed] Related Publications
Imatinib (IM) has been applied to the chronic phase of chronic myeloid leukemia (CML) and has great benefit on the prognosis of patients with CML. The function of drug efflux mediated by multidrug resistance protein-1 (MDR1) is considered as a main reason for IM drug resistance in CML cells. However, the exact mechanisms of MDR1 modulation in IM resistance of CML cells remain unclear. In the present study, long noncoding RNA (lncRNA) UCA1 was identified as an important modulator of MDR1 by a model system of leukemia cell lines with a gradual increase of MDR1 expression and IM resistance. Overexpression of UCA1 increased MDR1 expression to promote IM resistance of CML cells. Furthermore, for the first time, we demonstrated that UCA1 functions as a competitive endogenous (ceRNA) of MDR1 through completely binding the common miR-16. UCA1-MDR1 might be a novel target for enhancing the therapeutic efficacy of CML patients with IM resistance.

Shi D, Liu Y, Xi R, et al.
Caveolin-1 contributes to realgar nanoparticle therapy in human chronic myelogenous leukemia K562 cells.
Int J Nanomedicine. 2016; 11:5823-5835 [PubMed] Free Access to Full Article Related Publications
Chronic myelogenous leukemia (CML) is characterized by the t(9;22) (q34;q11)-associated Bcr-Abl fusion gene, which is an essential element of clinical diagnosis. As a traditional Chinese medicine, realgar has been widely used for the treatment of various diseases for >1,500 years. Inspired by nano-drug, realgar nanoparticles (NPs) have been prepared with an average particle size of <100 nm in a previous work. Compared with coarse realgar, the realgar NPs have higher bioavailability. As a principal constituent protein of caveolae, caveolin-1 (Cav-1) participates in regulating various cellular physiological and pathological processes including tumorigenesis and tumor development. In previous studies, it was found that realgar NPs can inhibit several types of tumor cell proliferation. However, the therapeutic effect of realgar NPs on CML has not been fully elucidated. In the present paper, it was demonstrated that realgar NPs can inhibit the proliferation of K562 cells and degrade Bcr-Abl fusion protein effectively. Both apoptosis and autophagy were activated in a dose-dependent manner in realgar NPs treated cells, and the induction of autophagy was associated with class I phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin pathway. Morphological analysis indicated that realgar NPs induced differentiation effectively in CML cells. Furthermore, it was identified that Cav-1 might play a crucial role in realgar NP therapy. In order to study the effects of Cav-1 on K562 cells during realgar NP treatment, a Cav-1 overexpression cell model was established by using transient transfection. The results indicated that Cav-1 overexpression inhibited K562 cell proliferation, promoted endogenic autophagy, and increased the sensitivity of K562 cells to realgar NPs. Therefore, the results demonstrated that realgar NPs degraded Bcr-Abl oncoprotein, while the underlying mechanism might be related to apoptosis and autophagy, and Cav-1 might be considered as a potential target for clinical comprehensive therapy of CML.

Dybko J, Jaźwiec B, Haus O, et al.
The Hasford Score May Predict Molecular Response in Chronic Myeloid Leukemia Patients: A Single Institution Experience.
Dis Markers. 2016; 2016:7531472 [PubMed] Free Access to Full Article Related Publications
The Sokal, Hasford, and EUTOS scores were established in different treatment eras of chronic myeloid leukemia (CML). None of them was reported to predict molecular response. In this single center study we tried to reevaluate the usefulness of three main scores in TKI era. The study group included 88 CML patients in first chronic phase treated initially with standard imatinib dose. All of them achieved major molecular response (MMR) in time points defined by European LeukemiaNet (ELN). 42 patients lost MMR in a median time of 47 months and we found a significant difference in MMR maintenance between intermediate-risk (IR) and low-risk (LR) patients assessed by Hasford score. All 42 patients were switched to second-generation TKI (2G-TKI) treatment. At 18 months of 2G-TKI therapy we have still found a significant difference in BCR-ABL transcript levels and MMR rate between IR and LR groups. We did not find any of the described differences discriminating patients by Sokal or EUTOS score. In this retrospective single center analysis we found Hasford score to be useful in predicting molecular response in first chronic phase of CML patients.

Zhang GF, Zhou M, Bao XB, et al.
Imatinib Mesylate Versus Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Chronic Myelogenous Leukemia.
Asian Pac J Cancer Prev. 2016; 17(9):4477-4481 [PubMed] Related Publications
PURPOSE: To compare the relative merits of imatinib and allogeneic hematopoietic stem cell transplantation (allo-HSCT) for chronic myelogenous leukemia (CML).
MATERIALS AND METHODS: This cohort study was designed to compare the outcomes of imatinib (n=292) versus allo-HSCT (n=141) for CML, the clinical data of these patients being retrospectively analyzed so as to compare the event free survival (EFS) and overall survival (OS) between these two groups with patients in the chronic phase (CP) and advanced phases, including accelerate (AP) and blast phases (BP).
RESULTS: (1) Patients treated with imatinib (278 in the CP) demonstrated superior EFS, OS, 5-year EFS and 5-year OS rates of 88.5% versus 70.0% (P<0.05), 93.2% versus 80.0% (P<0.05), 84% versus 75.0% (P<0.05) and 92% versus 79.0% (P<0.05), respectively, to those treated with allo-HSCT (120 patients in the CP). (2) Both treatments resulted in similar survival, with EFS and OS rates of 42.9% versus 47.6% (P>0.05), 42.9% versus 57.1% (P>0.05), respectively, for imatinib (14 patients in the AP and BP) and allo-HSCT (21 patients in the AP and BP).
CONCLUSIONS: Imatinib confers signi cant survival advantage (EFS and OS) for CML patients with CP compared with allo-HSCT treatment. However, the outcomes are equally good with both treatments in AP and BP patients.

Khoshtabiat L, Mahdavi M, Dehghan G, Rashidi MR
Oxidative Stress-Induced Apoptosis in Chronic Myelogenous Leukemia K562 Cells by an Active Compound from the Dithio- Carbamate Family.
Asian Pac J Cancer Prev. 2016; 17(9):4267-4273 [PubMed] Related Publications
Previous studies suggested that dithio-carbamates are potent apoptosis and anti-apoptosis inducing agents in various cancer cells. Here, the anti-proliferative and apoptosis inducing effects of a new derivative (2-NDC) from the dithio-carbamate family was examined in human leukemia K562 cells. We use thiazolyl blue tetrazolium bromide (MTT) to measure viability and cell growth inhibition. The 2-NDC showed effects on viability in a dose and time-dependent manner, inhibiting proliferation at concentrations of 10-30 μM after 24-48 hours of treatment and increasing values after 72 hours at 40-120 μM. The cytotoxic effect of the compound was calculated with an IC50 of 30 μM after 24-hour. Apoptosis induction was confirmed by acridine orange-ethidium bromide (AO/EtBr) staining, DNA fragmentation assay, flow cytometric assessment and also caspase-3 activation assay. Furthermore, enzymes level such as superoxide dismutase (SOD) and catalase (CAT) involved in oxidative stress were evaluated. The results of this study demonstrated insignificant increase of intracellular ROS levels for 24 hours and reduction after 48-72 hours. In addition to reduction of intracellular thiol, caspase-3 like activity was also decreased in a time-dependent manner in cells treated with 2-NDC. Thus 2-NDC can be considered as a good candidate for further pharmaceutical evaluations.

Gao X, Li J, Wang L, et al.
Bilineal Extramedullary Blast Crisis as an Initial Presentation of Chronic Myeloid Leukemia: A Case Report and Literature Review.
Am J Case Rep. 2016; 17:793-798 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the Philadelphia chromosome generated by the reciprocal translocation t(9: 22)(q34;q11). CML is usually diagnosed in the chronic phase. Blast crisis represents an advanced phase of CML. Extramedullary blast crisis as the initial presentation of CML with bone marrow remaining in chronic phase is an unusual event. Further, extramedullary blast crisis with T lymphoid/myeloid bilineal phenotype as an initial presentation for CML is extremely unusual. CASE REPORT Here, we report the case of a 49-year-old male with rapidly enlarged submandibular lymph nodes. Biopsy specimen from the nodes revealed a characteristic appearance with morphologically and immunohistochemically distinct myeloblasts and T lymphoblasts co-localized in 2 adjacent regions, accompanied by chronic phase of the disease in bone marrow. The presence of the BCR/ABL1 fusion gene within both cellular populations in this case confirmed the extramedullary disease represented a localized T lymphoid/myeloid bilineal blastic transformation of CML. After 3 courses of combined chemotherapy plus tyrosine kinase inhibitor treatment, the mass was completely regressed with a 3-log decrease in BCR/ABL1 transcript from baseline. Five months after the diagnosis, the patient showed diminished vision, hand tremors, and weakness of lower extremities. Flow cytometric immunophenotyping of cerebrospinal fluid revealed the presence of myeloid blasts. An isolated central nervous system relapse of leukemia was identified. Following high-dose systemic and intrathecal chemotherapy, the patient continued to do well. CONCLUSIONS The possibility of extramedullary blast crisis as an initial presentation in patients with CML should be considered. Further, an isolated central nervous system blast crisis should be considered if neurological symptoms evolve in patients who have shown a good response to therapy.

Jose J, Dhanya AT, Haridas KR, et al.
Structural characterization of a novel derivative of myricetin from Mimosa pudica as an anti-proliferative agent for the treatment of cancer.
Biomed Pharmacother. 2016; 84:1067-1077 [PubMed] Related Publications
The study was initiated to determine the anticancer activity of a novel compound isolated from the plant Mimosa pudica. The structure of the compound was identified as a derivative of myricetin having alkyl, hydroxy alkyl and methyl substitutions on the basis of spectral evidences (UV-vis, FT-IR, (1)H NMR and Mass spectra). The isolated compound was interpreted as 2-(2',6'-dimethyl-3',4',5'-alkyl or hydroxy alkyl substituted phenyl)-3-oxy-(alkyl or hydoxy alkyl)- 5,7-dihydroxy-chromen-4-one. In vitro evaluation of anticancer activity against human lung adenocarcinoma cell line (A549) and human erythroleukemic cell line (K562) were conducted using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. In vivo anticancer activity was determined against Dalton's Ascites Lymphoma (DAL) in Swiss albino mice. The mice were treated with intraperitoneal administration of the compound at 25mg/kg and 100mg/kg body weight and were compared with the normal, DAL control and standard drug cyclophosphamide treated groups. The histology revealed that the compound could protect the cellular architecture of liver and kidney. The results from the in vitro, in vivo and histological examinations confirmed the ethnopharmacological significance of the isolated compound and could be considered further for the development of an effective drug against cancer.

Kitanaka A
Management of advanced-phase chronic myeloid leukemia.
Rinsho Ketsueki. 2016; 57(10):1962-1971 [PubMed] Related Publications
The introduction of tyrosine kinase inhibitors (TKIs) has dramatically changed the management of patients with chronic myeloid leukemia (CML). Despite improved outcomes for most CML patients, disease progression from chronic phase (CP) to accelerated phase (AP) or blast phase (BP) occurs in 1-1.5% of cases per year with current TKI therapy. In addition, about 10-15% of newly diagnosed patients present in AP or BP. Even in the TKI era, the prognosis of patients with advanced-phase CML is not satisfactory. Although de novo AP patients who respond optimally to TKI have excellent outcomes, the prognosis of the remaining advanced-phase CML patients treated with TKI remains poor. For advanced-phase CML patients, allogeneic stem cell transplantation (allo-HSCT) is the only curative therapy. Patients eligible for allo-HSCT should first be treated with TKI with or without chemotherapy, in order to obtain reversion to CP, followed promptly by allo-HSCT. At present, the survival rates of patients undergoing allo-HSCT for advanced-phase CML are still disappointing. Prophylactic or preemptive administration of TKIs after allo-HSCT may improve long-term survival. Further investigation to improve the treatment outcomes of patients with advanced-phase CML is warranted.

Takahashi N
The importance of taking late cardiovascular toxicity induced by TKI into consideration in patients with CML.
Rinsho Ketsueki. 2016; 57(10):1956-1961 [PubMed] Related Publications
BCR-ABL tyrosine kinase inhibitor (TKI) has dramatically improved the prognosis of CML patients. Now, one of the most important factors with a marked effect on prognosis in CML patients is having a comorbidity. Recently, cardiovascular events (CVE) have been reported in some clinical trials as a late toxicity of TKI, which might be associated with off-target of TKI, ABL/ARG, PDGFR and VEGFR. Because TKI-associated CVE is one of the potentially lethal adverse events associated with TKI administration, hematologists must practice the "ABCDE steps" for CML patients treated with second generation TKI in collaboration with cardiologists.

Cervantes F, Correa JG, Pérez I, et al.
Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.
Ann Hematol. 2017; 96(1):81-85 [PubMed] Related Publications
To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR(4), MR(4.5), and MR(5) of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR(3). At the last follow-up, response was MR(3), MR(4), MR(4.5), and MR(5) in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Gardner JA, Peterson JD, Turner SA, et al.
Detection of CALR Mutation in Clonal and Nonclonal Hematologic Diseases Using Fragment Analysis and Next-Generation Sequencing.
Am J Clin Pathol. 2016; 146(4):448-55 [PubMed] Related Publications
OBJECTIVES: To describe three methods used to screen for frameshift mutations in exon 9 of the CALR gene.
METHODS: Genomic DNA from 47 patients was extracted from peripheral blood and bone marrow using the EZ1 DNA Blood Kit (Qiagen, Valencia, CA) and quantified by the Quant-iT PicoGreen dsDNA Assay Kit (Invitrogen, San Diego, CA). After clinical history, cytogenetics, and molecular tests, patients were diagnosed with either clonal or nonclonal hematologic diseases. CALR screening was primarily performed using fragment analysis polymerase chain reaction, then next-generation sequencing and Sanger sequencing.
RESULTS: Among the 18 patients diagnosed with clonal diseases, one had acute myeloid leukemia (positive for trisomy 8), and 17 had myeloproliferative neoplasms (MPNs), including chronic myeloid leukemia (CML), essential thrombocythemia (ET), primary myelofibrosis (PMF), and polycythemia vera (PV). Patients with CML were positive for the BCR-ABL1 fusion. Ten patients were positive for JAK2 (PMF, n = 1; ET, n = 2; PV, n = 7), and three were CALR positive (ET, n = 1; PMF, n = 2). Patients diagnosed with a nonclonal disease were negative for JAK2, BCR-ABL, and CALR mutations.
CONCLUSIONS: Screening for CALR mutations is essential in BCR-ABL-negative MPNs since it not only provides valuable diagnostic and prognostic information but also identifies potential treatment targets. Since this study describes the importance of screening for known and novel biomarkers, we described in detail three methods that could be easily integrated into a clinical laboratory.

Liu MY, Wang WZ, Liao FF, et al.
Selective and effective targeting of chronic myeloid leukemia stem cells by topoisomerase II inhibitor etoposide in combination with imatinib mesylate in vitro.
Cell Biol Int. 2017; 41(1):16-23 [PubMed] Related Publications
Imatinib mesylate (IM) and other BCR-ABL tyrosine kinase inhibitors (TKIs) have improved chronic myeloid leukemia (CML) patient survival markedly but fail to eradicate quiescent CML leukemia stem cells (LSCs). Thus, strategies targeting LSCs are required to induce long-term remission and achieve cure. Here, we investigated the ability of topoisomerase II (Top II) inhibitor etoposide (Eto) to target CML LSCs. Treatment with Eto combined with IM markedly induced apoptosis in primitive CML CD34(+) CD38(-) stem cells resistant to eradication by IM alone, but not in normal hematopoietic stem cells, CML and normal mature CD34(-) cells, and other leukemia and lymphoma cell lines. The interaction of IM and Eto significantly inhibited phosphorylation of PDK1, AKT, GSK3, S6, and ERK proteins; increased the expression of pro-apoptotic gene Bax; and decreased the expression of anti-apoptotic gene c-Myc in CML CD34(+) cells. Top II inhibitors treatment represents an attractive approach for targeting LSCs in CML patients undergoing TKIs monotherapy.

Fujimi A, Sakamoto H, Kanisawa Y, et al.
Pneumatosis intestinalis during chemotherapy with nilotinib in a patient with chronic myeloid leukemia who tested positive for anti-topoisomerase I antibodies.
Clin J Gastroenterol. 2016; 9(6):358-364 [PubMed] Related Publications
A 55-year-old man with several comorbidities including idiopathic interstitial pneumonia under long-term corticosteroid therapy, longstanding myocardial infarction, chronic heart failure, paroxysmal atrial fibrillation, gastro-esophageal reflux disease, constipation, and history of paralytic ileus, was diagnosed with chronic myelogenous leukemia (CML) in the chronic phase. He also tested positive for anti-topoisomerase I antibodies without clinical diagnosis of any connective tissue disease, including systemic sclerosis. Approximately 5 months after the initiation of nilotinib for CML, he developed upper abdominal distension with intermitting abdominal pain, and based on abdominal computed tomography findings, a diagnosis of pneumatosis intestinalis (PI) was made. Five courses of hyperbaric oxygen therapy quickly eliminated the PI and related symptoms without the cessation of nilotinib and, thereafter, additional oral prokinetic agents and non-absorbable antibiotics ensured the non-recurrence of PI. At 6 and 18 months after commencing nilotinib therapy, major and complete molecular response were achieved, respectively. It is suspected that both gastrointestinal hypokinesis related to the presence of anti-topoisomerase I antibodies and mucosal permeability due to corticosteroid therapy had existed. Thus, subsequent administration of nilotinib may have triggered PI by depressing gastrointestinal motility via the inhibition of c-kit.

Wang HY, Rashidi HH
The New Clinicopathologic and Molecular Findings in Myeloid Neoplasms With inv(3)(q21q26)/t(3;3)(q21;q26.2).
Arch Pathol Lab Med. 2016; 140(12):1404-1410 [PubMed] Related Publications
CONTEXT: - Inv(3)(q21q26)/t(3;3)(q21;q26.2) is the most common form of genetic abnormality of the so-called 3q21q26 syndrome. Myeloid neoplasms with 3q21q26 aberrancies include acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and blast crisis of myeloproliferative neoplasms. Recent advances on myeloid neoplasms with inv(3)/t(3;3) with regard to clinicopathologic features and novel molecular or genomic findings warrant a comprehensive review on this topic.
OBJECTIVE: - To review the clinicopathologic features and molecular as well as genomic alterations in myeloid neoplasms with inv(3)/t(3;3).
DATA SOURCES: - The data came from published articles in English-language literature.
CONCLUSIONS: - At the clinicopathologic front, recent studies on MDS with inv(3)/t(3;3) have highlighted their overlapping clinicopathologic features with and similar overall survival to that of inv(3)/t(3;3)-harboring AML regardless of the percentage of myeloid blasts. On the molecular front, AML and MDS with inv(3)/t(3;3) exhibit gene mutations, which affect the RAS/receptor tyrosine kinase pathway. Furthermore, functional genomic studies using genomic editing and genome engineering have shown that the reallocation of the GATA2 distal hematopoietic enhancer to the proximity of the promoter of ectopic virus integration site 1 (EVI1) without the formation of a new oncogenic fusion transcript is the molecular mechanism underlying these inv(3)/t(3;3) myeloid neoplasms. Although the AML and MDS with inv(3)/t(3;3) are listed as a separate category of myeloid malignancies in the 2008 World Health Organization classification, the overlapping clinicopathologic features, similar overall survival, and identical patterns at the molecular and genomic levels between AML and MDS patients with inv(3)/t(3;3) may collectively favor a unification of AML and MDS with inv(3)/t(3;3) as AML or myeloid neoplasms with inv(3)/t(3;3) regardless of the blast count.

Morishita S, Hagihara M, Itabashi M, et al.
Development of pulmonary arterial hypertension during oral dasatinib therapy for chronic myelogenous leukemia.
Rinsho Ketsueki. 2016; 57(8):999-1003 [PubMed] Related Publications
We present a 36-year-old woman who had been taking oral dasatinib for 3 years for the treatment of chronic myelogenous leukemia (CML). Although adverse events such as thrombocytopenia and pleural effusion developed, she showed a major molecular response (MMR) 22 months after the initiation of oral dasatinib administration, and the therapy was thus continued. Approximately 34 months after oral dasatinib initiation, she developed severe exertional dyspnea and had to be urgently hospitalized. There was no apparent pleural effusion increase, and neither imaging nor blood test results suggested pneumonia or other infections. Pulmonary arterial hypertension (PAH) was suspected on the basis of transthoracic echocardiography. PAH was then confirmed by right heart catheterization. Though dasatinib was discontinued on the day of hospitalization, pulmonary hypertension and heart failure progressed, and she did not respond to catecholamines or PDE5 (phosphodiesterase type 5) inhibitors. On the 4(th) hospital day, she experienced cardiopulmonary arrest and died 1 week later. Cases with PAH due to oral administration of dasatinib have been reported previously. However, cases showing the rapid progression documented in our patient are rare and we advocate that PAH be considered a potential adverse event associated with dasatinib therapy.

Chang WH, Huang HL, Huang WP, et al.
Armillaridin induces autophagy-associated cell death in human chronic myelogenous leukemia K562 cells.
Tumour Biol. 2016; 37(10):14291-14300 [PubMed] Related Publications
Armillaridin (AM) is an aromatic ester compound isolated from Armillaria mellea. Treatment with AM markedly reduced the viability of human chronic myelogenous leukemia K562, chronic erythroleukemia HEL 92.1.7, and acute monoblastic leukemia U937 cells, but not normal human monocytes, in a dose- and time-dependent manner. Treatment of K562 cells with AM caused changes characteristic of autophagy. Only a small amount of AM-treated K562 cells exhibited apoptosis. By contrast, AM treatment resulted in extensive apoptotic features in U937 and HEL 92.1.7 cells without evident autophagy. The autophagy of K562 cells induced by AM involved autophagic flux, including autophagosome induction, the processing of autophagosome-lysosome fusion and downregulation of BCL2/adenovirus E1B 19 kDa interacting protein 3 (BNIP3). By bcr-abl knockdown, the growth inhibition of K562 cells caused by AM was partially blocked, suggesting that AM-induced cell death might be a bcr-abl-dependent mode of autophagy-associated cell death. In conclusion, AM is capable of inhibiting growth and inducing autophagy-associated cell death in K562 cells, but not in normal monocytes. It may have potential to be developed as a novel therapeutic agent against leukemia.

Mahendrarajah N, Paulus R, Krämer OH
Histone deacetylase inhibitors induce proteolysis of activated CDC42-associated kinase-1 in leukemic cells.
J Cancer Res Clin Oncol. 2016; 142(11):2263-73 [PubMed] Related Publications
PURPOSE: Activated CDC42-associated kinase-1 (ACK1/TNK2) and epigenetic regulators of the histone deacetylase (HDAC) family regulate the proliferation and survival of leukemic cells. 18 HDACs fall into four classes (I-IV). We tested the impact of clinically relevant histone deacetylase inhibitors (HDACi) on ACK1 and if such drugs combine favorably with the therapeutically used ACK1 inhibitor Dasatinib.
METHODS: We applied the broad-range HDACi Panobinostat/LBH589 and the class I HDAC-specific inhibitor Entinostat/MS-275 to various acute and chronic myeloid leukemia cells (AML/CML). We also used the replicative stress inducer Hydroxyurea (HU), a standard drug for leukemic patients, and the apoptosis inducer Staurosporine (STS). To assess cytotoxic effects of HDACi, we measured cell cycle profiles and DNA fragmentation by flow cytometry. Western blot was employed to analyze protein expression and phosphorylation.
RESULTS: LBH589 and MS-275 induce proteolysis of ACK1 in CML and AML cells. Panobinostat more strongly induces apoptosis than Entinostat, and this correlates with a significantly pronounced loss of ACK1. STS and HU also propel the degradation of ACK1 in leukemic cells. Moreover, the caspase inhibitor z-VAD-FMK reduces ACK1 degradation in the presence of HDACi. Concomitant with the attenuation of ACK1, we noticed decreased phosphorylation of STAT3. Direct inhibition of ACK1 with Dasatinib also suppresses STAT3 phosphorylation. Furthermore, Dasatinib and HDACi combinations are effective against CML cells.
CONCLUSION: HDACs sustain the ACK1-STAT3 signaling node and leukemic cell growth. Consistent with their different effects on ACK1 stability or auto-phosphorylation, Dasatinib and HDACi combinations produce beneficial antileukemic effects.

Yousefi B, Shafiei-Irannejad V, Azimi A, et al.
PPAR-gamma in overcoming kinase resistance in chronic myeloid leukemia.
Cell Mol Biol (Noisy-le-grand). 2016; 62(8):52-5 [PubMed] Related Publications
Peroxisome proliferator-activated receptor gamma (PPARγ) plays key roles in regulating cellular differentiation, proliferation and apoptosis pathways. As such, they are considered promising targets for anticancer drug development, especially for breast cancer, multiple myeloma and hematologic malignancies. Chronic myeloid leukemia (CML) is a myeloproliferative disorder arising from an oncogenic Bcr-Abl tyrosine kinase. Inhibitors of this oncogene by small molecules such as imatinib are effective only in 75% of the patient's population. One of the potential strategies to overcome this resistance is to devise combination therapy protocols with other therapeutic agents including PPAR ligands. Since PPAR ligands are potentially interesting in different hematologic malignancies, this article will review the potential of PPAR ligands for use in CML treatment.

Farhadi E, Zaker F, Safa M, Rezvani MR
miR-101 sensitizes K562 cell line to imatinib through Jak2 downregulation and inhibition of NF-κB target genes.
Tumour Biol. 2016; 37(10):14117-14128 [PubMed] Related Publications
Imatinib mesylate (IM) is a frontline treatment in the early chronic phase of chronic myeloid leukemia (CML). However, intrinsic and acquired resistance against this drug has been defined and this issue has become a problem and a challenge in CML treatment. According to new findings, the inhibition of Janus kinase 2 (Jak2) in Bcr-Abl+ cells can promote apoptosis in IM-resistant cells. microRNAs (miRNAs) regulate the gene expression by targeting the messenger RNA (mRNA) for degradation. Recently, a growing body of evidence has implicated that dysregulation of miRNAs is associated with cancer initiation and development. In this report, we proposed that miRNA-101 targets Jak2 mRNA and regulates its expression and induces K562 leukemia cell apoptosis. Here, we transduced the K562 cell line with a miR-101-overexpressing vector and evaluated the Jak2 mRNA level. Our results showed that miR-101 overexpression in Bcr-Abl+ cells reduced the Jak2 mRNA level. Moreover, imatinib treatment and miR-101 upregulation led to miR-23a overexpression, which has putative binding site(s) on 3'-untranslated regions (3'-UTRs) of STAT5, CCND1, and Bcl-2 genes. Our results also indicated that miR-101 overexpression inhibited cell proliferation indicated by the MTT assay and promoted apoptosis detected via flow cytometry. Importantly, mRNA expression of NF-kappa B-regulated anti-apoptotic (Bcl-2, Bcl-xl, MCL-1, XIAP, and survivin) and proliferative (c-Myc and CCND1) genes was decreased. These findings suggest that miR-101 acts as a tumor suppressor by downregulating Jak2 expression and sensitizing K562 cells to imatinib. Therefore, restoration of miR-101 may be a therapeutic approach for CML treatment.

Hossain A, Gupta K, Mener A, Tabbara I
Case of CML lymphoid blast crisis presenting as bilateral breast masses.
BMJ Case Rep. 2016; 2016 [PubMed] Related Publications
A woman aged 42 years with a 1-month history of rapidly expanding bilateral breast masses presented with severe leucocytosis, anaemia, blurry vision, headaches and shortness of breath. Evaluation revealed chronic myeloid leukaemia in lymphoid blast crisis with extramedullary leukaemia involving her breasts.

Khan N, Afridi HI, Kazi TG, et al.
Correlation of Cadmium and Magnesium in the Blood and Serum Samples of Smokers and Non-Smokers Chronic Leukemia Patients.
Biol Trace Elem Res. 2017; 176(1):81-88 [PubMed] Related Publications
It was studied that cancer-causing processes are related with the disproportions of essential and toxic elements in body tissues and fluid. The purpose of the current study was to evaluate the levels of magnesium (Mg) and cadmium (Cd) in serum and blood samples of smokers and nonsmokers who have chronic myeloid (CML) and lymphocytic (CLL) leukemia, age ranged 31-50 years. For comparative study, age-matched smokers and nonsmoker males were chosen as controls/referents. The levels of elements in patient were analyzed before any treatment by atomic absorption spectrophotometer, after microwave assisted acid digestion. The validation of the method was done by using certified reference materials of serum and blood samples. The resulted data indicated that the adult male smokers and nonsmokers have two- to fourfold higher levels of Cd in the blood and sera samples as compared to the referents (p < 0.01), whereas two- to threefold lower levels of Mg was found in blood and serum samples of both types of leukemia patients as related to referent values. The resulted data indicates significant negative correlation among Mg and Cd in leukemia patients and smoker referents. Further studies are needed to clarify the role of these elements in pathogenesis of chronic leukemia.

Shah K, Parikh S, Rawal R
Tyrosine Kinase Inhibitors in Ph+ Chronic Myeloid Leukemia Therapy: a Review.
Asian Pac J Cancer Prev. 2016; 17(7):3025-33 [PubMed] Related Publications
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative hematopoietic stem cell disorder. Deregulated BCRABL fusion tyrosine kinase activity is the main cause of CML disease pathogenesis, making BCRABL an ideal target for inhibition. Current tyrosine kinase inhibitors (TKIs) designed to inhibit BCRABL oncoprotein activity, have completely transformed the prognosis of CML. Interruption of TKI treatment leads to minimal residual disease reside (MRD), thought to reside in TKIinsensitive leukaemia stem cells which remain a potential reservoir for disease relapse. This highlights the need to develop new therapeutic strategies for CML either as small molecule master TKIs or phytopharmaceuticals derived from nature to achieve chronic molecular remission. This review outlines the past, present and future therapeutic approaches for CML including coverage of relevant mechanisms, whether ABL dependent or independent, and epigenetic factors responsible for developing resistance against TKIs. Appearance of mutant clones along the course of therapy either preexisting or induced due to therapy is still a challenge for the clinician. A proposed invitro model of generating colony forming units from CML stem cells derived from diagnostic samples seems to be achievable in the era of high throughput technology which can take care of single cell genomic profiling.

Katagiri S, Tauchi T, Saito Y, et al.
Musculoskeletal pain after stopping tyrosine kinase inhibitor in patients with chronic myeloid leukemia: a questionnaire survey.
Rinsho Ketsueki. 2016; 57(7):873-6 [PubMed] Related Publications
We conducted a questionnaire survey to assess the state of patients with CML after discontinuation of TKI therapy. Nine of 27 patients developed musculoskeletal pain after TKI discontinuation. One had discontinued nilotinib and eight had discontinued imatinib therapy. Median time to symptom development after discontinuation was 2 weeks. Four experienced grade 3 symptoms as per the CTCAE ver. 4.0. One had pain persisting over a period of 21 months. There was a significant difference between patients with and without symptoms as regards female gender and the probability of persistent MMR. Awareness of this withdrawal syndrome after TKI discontinuation is imperative.

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