Global Proteomic Profiling of Pediatric AML: A Pilot Study

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3161
Nam H. K. Nguyen ◽  
Huiyun Wu ◽  
Haiyan Tan ◽  
Junmin Peng ◽  
Jeffrey E. Rubnitz ◽  

Acute Myeloid Leukemia (AML) is a heterogeneous disease with several recurrent cytogenetic abnormalities. Despite genomics and transcriptomics profiling efforts to understand AML’s heterogeneity, studies focused on the proteomic profiles associated with pediatric AML cytogenetic features remain limited. Furthermore, the majority of biological functions within cells are operated by proteins (i.e., enzymes) and most drugs target the proteome rather than the genome or transcriptome, thus, highlighting the significance of studying proteomics. Here, we present our results from a pilot study investigating global proteomic profiles of leukemic cells obtained at diagnosis from 16 pediatric AML patients using a robust TMT-LC/LC-MS/MS platform. The proteome profiles were compared among patients with or without core binding factor (CBF) translocation indicated by a t(8;21) or inv(16) cytogenetic abnormality, minimal residual disease status at the end of the first cycle of chemotherapy (MRD1), and in vitro chemosensitivity of leukemic cells to cytarabine (Ara-C LC50). Our results established proteomic differences between CBF and non-CBF AML subtypes, providing insights to AML subtypes physiology, and identified potential druggable proteome targets such as THY1 (CD90), NEBL, CTSF, COL2A1, CAT, MGLL (MAGL), MACROH2A2, CLIP2 (isoform 1 and 2), ANPEP (CD13), MMP14, and AK5.

2017 ◽  
Vol 92 (9) ◽  
pp. 845-850 ◽  
Brittany Knick Ragon ◽  
Naval Daver ◽  
Guillermo Garcia-Manero ◽  
Farhad Ravandi ◽  
Jorge Cortes ◽  

Chemotherapy ◽  
2020 ◽  
pp. 1-5
Orhan Kemal Yucel ◽  
Mustafa Serkan Alemdar ◽  
Unal Atas ◽  
Levent Undar

Although core-binding factor AML (CBF-AML) has a favorable outcome, disease relapses occur in up to 35% of patients. Minimal residual disease (MRD) monitoring is one of the important tools to enable us to identify patients at high risk of relapse. Real-time quantitative PCR allows MRD to be measured with high sensitivity in CBF-AML. If the patient with CBF-AML is in complete morphologic remission but MRD positive at the end of treatment, what to do for those is still uncertain. Preemptive intervention approaches such as allogeneic hematopoietic stem cell transplantation or intensive chemotherapy could be an option or another strategy might be just follow-up until overt relapse developed. Although using hypomethylating agents as a maintenance therapy has not been widely explored, here, we report a case with CBF-AML who was still positive for MRD after induction/consolidation therapies and whose MRD was eradicated by azacitidine maintenance.

Blood ◽  
2012 ◽  
Vol 120 (14) ◽  
pp. 2826-2835 ◽  
John A. Liu Yin ◽  
Michelle A. O'Brien ◽  
Robert K. Hills ◽  
Sarah B. Daly ◽  
Keith Wheatley ◽  

AbstractThe clinical value of serial minimal residual disease (MRD) monitoring in core binding factor (CBF) acute myeloid leukemia (AML) by quantitative RT-PCR was prospectively assessed in 278 patients [163 with t(8;21) and 115 with inv(16)] entered in the United Kingdom MRC AML 15 trial. CBF transcripts were normalized to 105ABL copies. At remission, after course 1 induction chemotherapy, a > 3 log reduction in RUNX1-RUNX1T1 transcripts in BM in t(8;21) patients and a > 10 CBFB-MYH11 copy number in peripheral blood (PB) in inv(16) patients were the most useful prognostic variables for relapse risk on multivariate analysis. MRD levels after consolidation (course 3) were also informative. During follow-up, cut-off MRD thresholds in BM and PB associated with a 100% relapse rate were identified: for t(8;21) patients BM > 500 copies, PB > 100 copies; for inv(16) patients, BM > 50 copies and PB > 10 copies. Rising MRD levels on serial monitoring accurately predicted hematologic relapse. During follow-up, PB sampling was equally informative as BM for MRD detection. We conclude that MRD monitoring by quantitative RT-PCR at specific time points in CBF AML allows identification of patients at high risk of relapse and could now be incorporated in clinical trials to evaluate the role of risk directed/preemptive therapy.

Blood ◽  
2013 ◽  
Vol 121 (12) ◽  
pp. 2213-2223 ◽  
Eric Jourdan ◽  
Nicolas Boissel ◽  
Sylvie Chevret ◽  
Eric Delabesse ◽  
Aline Renneville ◽  

Key Points In adult patients with core binding factor AML, intensified induction is not associated with a better outcome in the context of intensive postremission therapy. Minimal residual disease, rather than KIT or FLT3 gene mutations, should be used to identify core binding factor AML patients at higher risk of relapse.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 543-543
John Ahman Liu-Yin ◽  
Sarah B. Daly ◽  
Michelle A. Sale ◽  
Stuart Green ◽  
Khalid Tobal ◽  

Abstract The clinical value of serial Minimal Residual Disease (MRD) monitoring in core binding factor (CBF) positive patients was prospectively assessed in the AML-15 Trial which opened in July 2002. The trial compared 3 induction regimens (DA V/S ADE V/S FLAG Ida), followed by randomisation in consolidation (courses 3 and 4) to either MACE or 2 doses of Ara-C (3g/m2 or 1.5g/m2) and to stop or have a 5th course (Ara-C 1.5g/m2). Patients were also randomised to receive Gemtuzumab Ozogamicin (3mg/m2) at induction and/or consolidation. Over 2500 patients have so far been recruited, with 271 CBF patients (155 t(8;21), 116 inv (16)). Complete remission (CR) and relapse rates (RR) at 4 years were 95% and 19% respectively. CBF transcripts (AML1-ETO for t(8;21), CBFB-MYH11 for inv(16)) from bone marrow (BM) and peripheral blood (PB) were measured by real-time quantitative PCR (RQ-PCR) on the 7900 HT ABI machine, at presentation, after each course of chemotherapy and 3 monthly during remission for 2 years. CBF copies were normalised to ABL gene and expressed per 105ABL. The sensitivity of the RQ-PCR assay was 10−5. Data were analysed in 47 relapsed patients and in 92 patients who were in remission for >1 year. In 66 patients, where the reduction of initial CBF transcript level in BM, following induction chemotherapy, was measured, only 1 of 32 patients with >3 log reduction at remission whereas 20/34 patients with <3 log reduction have relapsed, giving relapse rates of 3% and 61% respectively, (2p<0.00001). With respect to BM post induction transcript levels, in the t(8;21) group (n=50), patients with <500 AML1-ETO copies had a 18% RR compared to 62% for patients with >500 copies (2p=0.003) and in the inv (16) patients (n=38), the RR were 8% and 58% respectively for CBFB-MYH11 copies lower or higher than 100 (2p=0.004). After consolidation and during remission, BM and PB transcript levels were also highly predictive of relapse risk. In t(8;21) patients, all 7 with BM AML1-ETO level >500 copies but only 3/45 patients with <500 copies relapsed (RR 100% V/S 9%, 2p<0.0001). Moreover all 12 patients with PB level >50 copies and only 2/52 patients negative for or with <50 AML1-ETO copies relapsed (RR 100% V/S 4%, 2p <0.00001). In inv (16) patients, 13/13 with >100 CBFB-MYH11 copies in BM and 3/25 patients with <100 copies relapsed (RR 100% V/S 9%, 2p<0.00001). In PB, any positive level resulted in relapse in 18/18 patients compared to 2/29 (RR 7%) with a negative MRD for CBFB-MYH11 (2p<0.00001). The interval between molecular and clinical relapse was ≥3 months and there was a significant correlation between BM and PB MRD levels post induction and at first positivity after consolidation (r>0.40, p<0.05). We conclude that MRD monitoring in CBF AML allows risk stratification based on treatment response, and can predict relapse, thus opening the way to risk-directed or pre-emptive therapy. We propose that MRD monitoring by RQ-PCR should be an integral part of the management of CBF positive AML.

2017 ◽  
Vol 59 (9) ◽  
pp. 2188-2200 ◽  
Zaw Min Oo ◽  
Anuradha Illendula ◽  
Jolanta Grembecka ◽  
Charles Schmidt ◽  
Yunpeng Zhou ◽  

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