scholarly journals Comparison of the Transcriptomic Signature of Pediatric Vs. Adult CML and Normal Bone Marrow Stem Cells

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4246-4246 ◽  
Author(s):  
Hee-Don Chae ◽  
Lara C. Murphy ◽  
Michele Donato ◽  
Alex G. Lee ◽  
E. Alejandro Sweet-Cordero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Differentially Expressed Genes ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Differentially Expressed ◽  
False Discovery ◽  
Cd34 Cells ◽  
Transcriptomic Signature

Abstract Introduction Pediatric chronic myeloid leukemia (CML) accounts for 10 to 15% of children with myeloid leukemia and 2 to 9% of all pediatric leukemias. Prior to the discovery of tyrosine kinase inhibitors (TKI) such as imatinib, stem cell transplantation was the only curative treatment for both adults and children with CML. However, due to the small numbers of patients, standardized treatment approaches for pediatric CML have not been established. There are several unique characteristics of CML diagnosed in children and adolescents, and young adults (AYA; 16-29 years), compared to adults. Children and AYA with CML present with a higher white blood count and have larger spleens, higher peripheral blast counts, and lower hemoglobin levels, suggesting that the biology of pediatric CML is different than adult CML. In addition, potential side effects of TKIs unique to pediatric CML patients include impaired bone growth, fertility and immune function, however none have been extensively studied. We hypothesize that the differences in clinical presentation of pediatric CML patients are due to unique molecular characteristics that are absent in adult CML patients. To test this hypothesis, we studied the transcriptomic signature of pediatric CD34+ CML cells compared to adult CML and normal age-matched bone marrow CD34+ cells. Methods CD34+ cells were isolated from pediatric CML (n=7), adult CML (n=8), pediatric normal (n=2) and adult normal (n=3) bone marrow samples. Total RNA was isolated from cells, and then cDNA libraries were generated. Prepared libraries were sequenced on the Illumina HiSeq 4000 instrument. We aligned reads using the HISAT2 alignment software, and mapped to genes with HT-Seq. We removed genes that had zero reads across all the samples, resulting in a set of 4,696 genes that were detected in one or more samples. In case of technical replicates, we used mean of replicates. We performed three differential expression comparisons with edgeR: (1) Pediatric CML vs Adult CML, (2) Adult CML vs Adult Normal, and (3) Pediatric CML vs Pediatric Normal. We used a False Discovery Rate (FDR) of £ 20% and absolute log2 fold-change ³ 1 for selecting differentially expressed genes in each comparison. We used Fisher's exact test to identify significant KEGG pathways for the differentially expressed genes in each comparison. Results Pediatric CML vs Adult CML We found 24 differentially expressed genes (15 over- and 9 under-expressed). Though no pathway was found to be significant at the false discovery rate (FDR) £ 20%, we identified a number of sub-pathways that are relevant. For example, the Chemokine Signaling pathway shows at the top of the list (ordered by raw p-value) because of two genes, XCR1 and HCK, associated with VEGF and MAPK pathways involved in cell proliferation, angiogenesis, DNA repair, and cancer pathogenesis. Adult CML vs Adult Normal We found 60 genes (30 over- and 30 under-expressed) differentially expressed when comparing adult CML patients to normal adults. Ten genes overlapped with 24 genes we identified when comparing pediatric and adult CML patients. We found 11 pathways as significant at FDR £ 10%. Multiple pathways, including Cell adhesion, allograft rejection, Graft versus Host Disease, and Type I diabetes pathways, showed downregulation of MHC, with subsequent downstream reduction in expression of apoptosis-related genes. The IL-17 pathway makes sense, as MAPK, well-known to be associated with various cancers, is down-regulated. Lastly, in the NK pathway the gene DAP12 is up-regulated. This gene is known as a tyrosine kinase binding protein, and although tyrosine kinase inhibitors are the standard treatment for CML, the role of DAP12 in relation to leukemia has not yet been described. Pediatric CML vs Pediatric Normal We found 509 genes (350 over- and 159 under-expressed) differentially expressed in pediatric CML patients compared to normal. Interestingly, transcriptional regulators are differentially enriched in the hematopoietic stem cell differentiation function group including GATA1, GATA2, KLF1 and KLF2. RFC is down-regulated. RFC is a mismatch repair gene known to be involved in colorectal cancer. Many of the significant pathways are involved in glucose and fatty acid metabolism. Our pilot study identified novel molecular features of pediatric CML bone marrow stem cells, providing new insights into the novel biomarkers and pathogenesis of pediatric CML. Disclosures Gotlib: Blueprint Medicines: Consultancy, Honoraria, Research Funding; Promedior: Research Funding; Deciphera: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Kartos: Consultancy; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Prognostic Factors in Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors- Single Center Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2210-2210 ◽  
Author(s):  
Kajetana Foryciarz ◽  
Tomasz Sacha ◽  
Izabela Florek ◽  
Sylwia Czekalska ◽  
Magdalena Zawada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Population Based ◽  
Molecular Response ◽  
First Line

Abstract Abstract 2210 Poster Board II-187 Background: Imatinib mesylate (IM), a targeted inhibitor of the BCR-ABL tyrosine kinase, is widely used to treat chronic myeloid leukemia (CML). However, considerable number of patients fails to achieve or loose complete cytogenetic response (CCyR) or major molecular response (MMR). The mechanisms of failure in the majority of cases are unknown. Identification of patients who may subsequently fail to respond to imatinib would provide a considerable aid to clinical management. Few long-term retrospective population-based data on the outcome of these patients are available. Aims: To identify prognostic factors that can predict failure of treatment with tyrosine kinase inhibitors (TKI), and to optimise CML therapy after first line TKI failure. Patients and methods: The retrospective population-based analysis included 138 patients (68 females, 70 males, median age 47 yrs) in early chronic phase (ECP) (n=63), late chronic phase (LCP) (n=60) or accelerated phase (AP) (n=15) of CML. All enrolled patients were treated with IM 400mg/day for CP or 600 mg/day for AP as a first line TKI. Patients were monitored for cytogenetic and molecular response every 6 and 3 months respectively using conventional cytogenetic on bone marrow and quantitative PCR (RQ-PCR) on peripheral blood. Results of RQ-PCR were expressed as a ratio of BCR-ABL/ABL% [IS]. Definitions of CCyR, MMR as well as CP and AP were consistent with European LeukemiaNet recommendations. The analyzed factors included: time to complete hematologic remission (CHR), time to CCyR, time to MMR and additional cytogenetic abnormalities in Ph positive cells [ACA Ph(+)] during first line IM treatment and % of CCyR and MMR during second line TKI treatment. To estimate probability of CCyR and MMR cumulative incidence analysis was used. Cytogenetic and molecular progression free survival (PFS) was estimated by Kaplan-Meier analysis. Results: Probability of CCyR for the analyzed group was 55%, 60% and 62% after 12, 18 and 24 months of treatment with IM respectively. Probability of cytogenetic PFS was 92%, 83%, 81% and 76% in 12, 18, 24 and 36 months respectively. There was observed statistically significant correlation between probability of achievement of CCyR, MMR and the following: time to CHR, time to imatinib introduction, phase of the disease and ACA Ph(+). No correlation between probability of CCyR, MMR and age, sex, Sokal and Hasford risk factors was observed. 1) Early CHR in up to 8 weeks after diagnosis (dx) predicted CCyR and MMR achievement irrespective of treatment schedule to CHR (p<0,0001) (Fig 1.). 2) Early IM introduction up to 4 months since dx increased probability of CCyR and MMR in 12 and 18 months respectively (p<0,0001). 3) Patients in LCP were significantly less likely to obtain CCyR and MMR comparing to ECP and results in this group were similar to AP patients (p=0,0004) (Fig. 2). 4) Early CCyR up to 6 months after starting IM increased probability of MMR (p<0,0001). 5) ACA Ph(+) were confirmed as an adverse prognostic factor regarding to achieving (p=0,005) and maintaining (p=0,01) of CCyR. 6) Treatment with higher dose of IM predicted better outcome when ACA Ph(+) at diagnosis and/or at least 10% of blasts in bone marrow or peripheral blood at dx were considered as AP criteria. 7) Among patients after IM failure those treated with 2G TKI were more likely to achieve and maintain CCyR (52%) than those with escalation of IM (24%) (p=0,02). Conclusions: These data suggest need of 1) therapy intensification from the very moment of diagnosis, 2) early achievement of CHR, 3) early IM introduction (<4 months from dx in analysed population), 4) the precise defining of AP with rigid criteria may result in better outcome. 5) Relative risk (Sokal and Hasford) relationship with treatment results seems to be not sufficient when IM is introduced after a long time since diagnosis. 5) Treatment switch to 2G TKI but not imatinib escalation after first line IM treatment failure is proposed to be an optimal treatment standard. Disclosures: Foryciarz: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Sacha:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Florek:BMS: Research Funding; Novartis: Research Funding. Czekalska:BMS: Research Funding; Novartis: Research Funding. Zawada:Novartis: Research Funding; BMS: Research Funding. Skotnicki:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Differentially expressed genes responsible for insensitivity of CD34+ cells to kinase inhibitors in patients with chronic myeloid leukemia

2013 ◽  
Vol 7 (S2) ◽  
Author(s):  
Caroline FA Moreira-Nunes ◽  
Tereza CB Azevedo ◽  
Ana CS Beltrão ◽  
Larissa TVM Francês ◽  
Rodrigo GMA Sousa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Differentially Expressed Genes ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Differentially Expressed ◽  
Cd34 Cells

scholarly journals Comparison of the Transcriptomic Signatures in Pediatric and Adult CML

Cancers ◽  
2021 ◽  
Vol 13 (24) ◽  
pp. 6263
Author(s):  
Minyoung Youn ◽  
Stephanie M. Smith ◽  
Alex Gia Lee ◽  
Hee-Don Chae ◽  
Elizabeth Spiteri ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Rna Sequencing ◽  
Differentially Expressed Genes ◽  
High Throughput ◽  
Myeloid Leukemia ◽  
Differentially Expressed ◽  
Molecular Characteristics ◽  
Healthy Controls ◽  
Cd34 Cells ◽  
Transcriptomic Signature

Children with chronic myeloid leukemia (CML) tend to present with higher white blood counts and larger spleens than adults with CML, suggesting that the biology of pediatric and adult CML may differ. To investigate whether pediatric and adult CML have unique molecular characteristics, we studied the transcriptomic signature of pediatric and adult CML CD34+ cells and healthy pediatric and adult CD34+ control cells. Using high-throughput RNA sequencing, we found 567 genes (207 up- and 360 downregulated) differentially expressed in pediatric CML CD34+ cells compared to pediatric healthy CD34+ cells. Directly comparing pediatric and adult CML CD34+ cells, 398 genes (258 up- and 140 downregulated), including many in the Rho pathway, were differentially expressed in pediatric CML CD34+ cells. Using RT-qPCR to verify differentially expressed genes, VAV2 and ARHGAP27 were significantly upregulated in adult CML CD34+ cells compared to pediatric CML CD34+ cells. NCF1, CYBB, and S100A8 were upregulated in adult CML CD34+ cells but not in pediatric CML CD34+ cells, compared to healthy controls. In contrast, DLC1 was significantly upregulated in pediatric CML CD34+ cells but not in adult CML CD34+ cells, compared to healthy controls. These results demonstrate unique molecular characteristics of pediatric CML, such as dysregulation of the Rho pathway, which may contribute to clinical differences between pediatric and adult patients.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

Individual Gene Expression Profiling of Bone Marrow CD34 Cells in Acquired Severe Aplastic Anemia (aSAA) in Children.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 978-978 ◽  
Author(s):  
Bernd Hubner ◽  
Sylvia Merk ◽  
Sonja Rauhut ◽  
Martin Dugas ◽  
Torsten Haferlach ◽  
...  
Keyword(s):  
Gene Expression ◽  
Stem Cells ◽  
Bone Marrow ◽  
Differentially Expressed Genes ◽  
Expression Profiling ◽  
Cell Metabolism ◽  
Cell Communication ◽  
Differentially Expressed ◽  
Cd34 Cells ◽  
The Individual

Abstract Acquired SAA in children is a rare, life-threatening disease characterized by pancytopenia and bone marrow hypocellularity. There is good clinical and laboratory evidence that a T-cell mediated immune attack against stem and progenitor cells plays an important role in the pathogenesis of SAA. However, due to the paucity of residual CD34 positive cells at diagnosis still only little is known about the stem cells and their response to the autoimmune attack in SAA in children. To further investigate the characteristics of CD34 cells in SAA we compared the individual transcriptomes of CD34 cells of 9 newly diagnosed, untreated pediatric SAA patients with 8 pediatric healthy controls. Hematopoietic stem cells were isolated with high efficiency from bone marrow by Ficoll density centrifugation and subsequent affinity purification using Dynabeads (Dynal, Invitrogen). Expression profiling experiments were performed using the two cycle amplification system and the HG-U133 plus 2.0 array (Affymetrix). Gene expression data were analyzed using R 2.3.0 and Bioconductor 1.8. packages (Affymetrix, multtest). Raw data were normalized using robust multiarray average (RMA) algorithm. Probe sets with “absent” calls in more than 50% of samples in the smaller group were identified and omitted from further analysis. To determine differentially expressed genes, t-test was applied. P value adjustments for multiple comparisons were done using the step-up false discovery rate (FDR) controlling method proposed by Benjamini and Hochberg. Overall 402 genes were differentially expressed in children with SAA compared to controls (p &lt; 0.05), 288 genes were downregulated and 114 were upregulated. Gene ontology analyses (FatiGO) indicated that biological processes in CD34 cells are significantly affected in pediatric SAA by mainly downregulation of genes for cell metabolism (78 down, 30 up), cell communication/adhesion (48 down, 25 up), growth and differentiation (15 down, 4 up) and stress response (16 down, 3 up). Unexpectedly only very few genes involved in cell death/apoptosis (5 down, 4 up) were differentially expressed. Genes encoding for DNA/RNA binding proteins (28 down, 14 up) and ion binding proteins (47 down, 18 up) were also mainly downregulated. Despite the extremely low numbers of residual CD34 cells present in the bone marrow of children with untreated SAA we were able to analyze the individual transcriptome pattern of single patients. These patterns showed homogeneously and significantly different gene expressions in the group of affected children when compared to controls. Genes involved in apoptosis seem to be less altered in there expression than expected from adult data. These observation might be consistent with the major clinical finding in these children of almost empty bone marrows where most of the apoptotic cell death has already taken place. In the tiny population of “survivors” most of the differentially expressed genes are involved in cell metabolism and cell communication or adhesion. These unexpected results provide new hints for further investigations regarding the involvement of CD34 cells in the pathogenesis of childhood aSAA.

Microenvironmental Factors Determine the Sensitivity of Acute Myeloid Leukemia Cells to Tyrosine Kinase Inhibitors.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1630-1630
Author(s):  
Akira Shimada ◽  
Shelley Orwick ◽  
Hiroyuki Fujisaki ◽  
Dario Campana ◽  
Sharyn D. Baker
Keyword(s):  
Bone Marrow ◽  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Protective Effect ◽  
Tyrosine Kinase Inhibitors ◽  
Direct Contact ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Soluble Factors ◽  
Acute Myeloid

Abstract There is an increasing body of evidence indicating that the bone marrow microenvironment can generate drug resistance in acute leukemia. The mechanisms underlying this effect have not yet been elucidated; signals triggered by direct contact with extracellular matrix components and by mesenchymal cell (MSC)-secreted factors have been implicated. The protective effect of the microenvironment has been primarily observed for classical chemotherapeutic drugs. Recent reports, however, indicate that this can also occur with molecularly targeted therapies. Thus, it was shown that interleukin (IL)-7 desensitizes BCR-ABL+ leukemic cells to imatinib (Williams RT et al. Genes Dev 2007) and MSC-conditioned media protects BCR-ABL+ cells to imatinib and nilotinib (Weisberg E at al. Mol Cancer Ther, 2008). Several tyrosine kinase inhibitors are in clinical development for the treatment of acute myeloid leukemia (AML). The aim of this study was to determine whether bone marrow MSC affected the sensitivity of AML cells to 3 promising tyrosine kinase inhibitors (sorafenib, sunitinib, and midostaurin) and, if so, to begin to elucidate the underlying mechanisms. Using proliferation assays, we found that 3 AML cells lines (MV4-11, U937, and THP1) were significantly less sensitive to the tyrosine kinase inhibitors when cultured in the presence of bone marrow-derived MSC for 24h before exposure to drugs for 72h. In experiments with MV4-11, IC50 increased from 4.7 nM to 55 nM for sorafenib, from 10 nM to 110 nM for sunitinib, and from 28 nM to 135 nM for midostaurin; in experiments with U937, IC50 increases were 5.1 μM to 11 μM, 6.2 μM to &gt; 10 μM, and 230 to &gt; 1000 nM for each drug; and in experiments with THP1, they were 6.3 μM to 11 μM, 2.2 μM to &gt; 10 μM, and 211 nM to 996 nM. Coculture with MSC also reduced sorafenib- and sunitinib-induced apoptosis by &gt; 60%. Interestingly, drug resistance increased even further after coculturing the cell lines with MSC for 4 weeks or longer: sunitinib had virtually no effect on the proliferation of MV4-11 cells at concentrations of up to 100 nM, and on THP-1 cells at 10 μM. To determine whether the induction of drug resistance was dependent on the direct contact of AML cells with MSC, we tested sensitivity to sorafenib after separating MV4-11cells from MSC with transwell inserts. Under these conditions, the protective effect of MSC was lessened but not abrogated. These results indicated that direct contact with MSC was not an absolute requirement for induction of drug resistance and that MSC-secreted soluble factors might be, at least in part, involved. We therefore determined the soluble factors secreted by MSC using a multiplex assay and tested whether their secretion was augmented by contact with AML cells. MSC secreted IL-6 (230 pg/mL), IL-8 (1880 pg/mL), and VCAM-1 (30 pg/mL). When cocultured with MV4-11, U937 and THP-1 cells for 24h, IL-6 secretion increased 1.3 to 1.8-fold, IL-8 increased 1.5 to 2.6-fold, and VCAM-1 increased 2.2 to 5.6-fold; after 72 of coculture, dramatically elevated levels of IL-6 (2140–3869 pg/mL), IL-8 (4296–8068 pg/mL), and VCAM-1 (5109–6389 pg/mL) were observed. The effects of these and other MSC-derived factors on the sensitivity of AML cells lines and primary AML cells to tyrosine kinase inhibitors are being tested. These results indicate that the anti-AML effect of tyrosine kinase inhibitors is strongly inhibited by bone marrow MSC cells, and support the concept that the microenvironment is an important determinant of resistance to these agents in leukemia. We suggest that the development of agents that interfere with the interaction between AML cells and MSC, and with the molecular mechanisms underlying this protective effect of MSC is a crucial step to improve cure rates.

scholarly journals Statins Enhance the Molecular Response in Chronic Myeloid Leukemia When Combined with Tyrosine Kinase Inhibitors

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5543
Author(s):  
Hyeok-Jae Jang ◽  
Young-Min Woo ◽  
Kazuhito Naka ◽  
Jong-Ho Park ◽  
Ho-Jae Han ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Inhibitory Effects ◽  
Growth Inhibitory ◽  
Cd34 Cells

Previous studies have suggested that statins can be repurposed for cancer treatment. However, the therapeutic efficacy of statins in chronic myeloid leukemia (CML) has not yet been demonstrated. In this study, we retrospectively evaluated the outcomes of 408 CML patients who underwent imatinib therapy. The deep molecular response rates in patients treated with the statin/TKI combination were significantly higher than those in patients treated with TKI alone (p = 0.0016). The statin/TKI combination exerted potent cytotoxic effects against wild-type and ABL1 mutant CML, BaF3, and K562/T315I mutant cells. Furthermore, the statin/TKI combination additively inhibited the colony-forming capacity of murine CML-KLS+ cells in vitro. In addition, we examined the additive growth-inhibitory effects of the statin/tyrosine kinase inhibitor (TKI) combination against CML patient-derived CD34+ cells. The growth-inhibitory effects of the statin/imatinib combination against CD34+/CML primary cells were higher than those against CD34+/Norm cells (p = 0.005), suggesting that the combination of rosuvastatin and imatinib exerted growth-inhibitory effects against CML CD34+ cells, but not against normal CD34+ cells. Furthermore, results from RNA sequencing of control and statin-treated cells suggested that statins inhibited c-Myc-mediated and hematopoietic cell differentiation pathways. Thus, statins can be potentially repurposed to improve treatment outcomes in CML patients when combined with TKI therapy.

scholarly journals Proteomics Analysis Reveals Protein Panels That Are Associated with Prediction to Tyrosine Kinase Inhibitors Response, Bone Marrow Transplant, Survival and Disease Outcome of Chronic Myeloid Leukemia Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5434-5434
Author(s):  
Ayodele Alaiya ◽  
Mahmoud Aljurf ◽  
Zakia Shinwari ◽  
Fahad Z. Alsharif ◽  
Hazza A. Alzahrani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Personalized Medicine ◽  
Tyrosine Kinase ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
The Other ◽  
Disease Outcome

Abstract Clinical and molecular diagnosis of most hematological malignancies including Chronic Myeloid Leukemia (CML) can be accurately made. However, prediction of treatment response and estimation of disease survival period eludes the currently available tools for patient care. Quantitative expression proteomics can potentially be developed as effective tool to monitor therapy response towards achieving personalized medicine for CML patients. We have over 10 years follow up period for some of the CML patients, and the majorities of them are alive and doing well on Imatinib. On the other hand, a small fraction of the patients were switched to alternative Tyrosine Kinase Inhibitors (TKI) and some underwent bone marrow transplants (BMT). Our follow up results stratified all 37 analyzed newly diagnosed CP-CML patients into 5 distinct cohorts including 52% on Imatinib, 12% on Nilotinib, 9% on Dasatinib, and 15% BMT, while 12% of the patients had disease-related mortality. Kaplan-Meier survival curve showed no significant difference between all patients on TKI and BMT that were alive under a follow up period of 4-11 years compared. On the other hand 3 of 4 patients had disease related deaths less than 2 years of diagnosis. Only one patient survived for almost 10 years (Figure 1). Besides survival analysis, peripheral blood samples obtained from the patients at time of diagnosis were subjected to expression proteome analysis using label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). A subset of significantly differentially expressed proteins was able to distinctively discriminate samples into their respective treatment response and disease outcome groups based on unique protein expression signatures (P<0.05 and > 2- ∞- fold change, (Figure 2). Some of the identified proteins were implicated in hematological diseases including CML as potential biomarkers using Ingenuity Pathway Analysis. These protein signatures once validated in larger sample cohorts might be capable of prediction of molecular response, choice of therapy and disease outcome for CML patients. Therefore; allowing for identification of would be high risk patients that might potentially benefit from aggressive treatment at point of diagnosis pre initiation of conventional therapy. Altogether our findings indicate that analysis of panel of protein markers have the potential of clinical utility for prediction of response to therapy, disease survival and objective prognostication of disease outcome, thus bringing personalized medicine closer to CML patients. Disclosures No relevant conflicts of interest to declare.

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