MYC protein expression is an important prognostic factor in acute myeloid leukemia

Abstract As new drugs targeting MYC show clinical activity in acute myeloid leukemia (AML), understanding MYC expression in AML is of critical importance. We assessed MYC protein expression by immunohistochemistry in bone marrow of patients with untreated AML (n = 265). Overall, 90% of patients demonstrated MYC overexpression and MYC immunopositivity ≤6% was associated with superior complete remission (CR) duration of 23 months versus 12 months for MYC immunopositivity >6% (p = .028). Among 241 patients at higher risk for relapse, including those ≥55 years of age and patients with intermediate- and high-risk AML, MYC immunopositivity ≤6% conferred significantly superior median overall survival (OS) (24 versus 13 months; p = .042), event-free survival (EFS) (14 versus 6 months; p = .048), and relapse-free survival (RFS) (25 versus 12 months; p = .024). The prognostic impact of MYC-immunopositivity was retained on multivariate analysis of OS, EFS, and RFS. We conclude that MYC immunopositivity is an important prognostic factor in patients with untreated AML, particularly those at higher risk for relapse.

[1]  J. Sierra,et al.  CD34+ Cell Selection versus Reduced-Intensity Conditioning and Unmodified Grafts for Allogeneic Hematopoietic Cell Transplantation in Patients Age >50 Years with Acute Myelogenous Leukemia and Myelodysplastic Syndrome . , 2018, Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation.

[2]  J. Sierra,et al.  CD34+ selection vs. reduced-intensity conditioning and unmodified graft for allogeneic hematopoietic cell transplantation in patients with AML and MDS > 50 years , 2018 .

[3]  M. Dawson,et al.  A Phase I Study of GSK525762, a Selective Bromodomain (BRD) and Extra Terminal Protein (BET) Inhibitor: Results from Part 1 of Phase I/II Open Label Single Agent Study in Patients with Acute Myeloid Leukemia (AML) , 2017 .

[4]  J. Foran,et al.  Older Patients With Acute Myeloid Leukemia: Treatment Challenges and Future Directions. , 2017, The Ochsner journal.

[5]  J. Nilsson,et al.  Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers , 2017, British journal of haematology.

[6]  S. Swerdlow WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues , 2017 .

[7]  A. Mansoor,et al.  Acute myeloid leukaemia: expression of MYC protein and its association with cytogenetic risk profile and overall survival , 2017, Hematological oncology.

[8]  G. He,et al.  2016 Revision to the WHO classification of acute myeloid leukemia , 2017, Journal of translational internal medicine.

[9]  M. Konopleva,et al.  Persistence of minimal residual disease assessed by multiparameter flow cytometry is highly prognostic in younger patients with acute myeloid leukemia , 2017, Cancer.

[10]  C. Bueso-Ramos,et al.  Double minute chromosomes in acute myeloid leukemia, myelodysplastic syndromes, and chronic myelomonocytic leukemia are associated with micronuclei, MYC or MLL amplification, and complex karyotype. , 2016, Cancer genetics.

[11]  Z. Estrov,et al.  Acute myeloid leukemia with MYC rearrangement and JAK2 V617F mutation. , 2015, Cancer genetics.

[12]  C. Craddock,et al.  In patients older than 55 years with AML in first CR, should we search for a matched unrelated donor when an old sibling donor is available? , 2015, Bone Marrow Transplantation.

[13]  M. McArthur,et al.  hnRNP K Is a Haploinsufficient Tumor Suppressor that Regulates Proliferation and Differentiation Programs in Hematologic Malignancies. , 2015, Cancer cell.

[14]  H. Kantarjian,et al.  TP53 overexpression is an independent adverse prognostic factor in de novo myelodysplastic syndromes with fibrosis , 2015, British journal of haematology.

[15]  J. León,et al.  MYC as therapeutic target in leukemia and lymphoma , 2015 .

[16]  R. Stone Should older adults with AML receive post-remission therapy? , 2015, Best practice & research. Clinical haematology.

[17]  E. Estey,et al.  Prognostic significance of NPM1 mutations in the absence of FLT3-internal tandem duplication in older patients with acute myeloid leukemia: a SWOG and UK National Cancer Research Institute/Medical Research Council report. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Sheng Wei,et al.  c-Myc plays part in drug resistance mediated by bone marrow stromal cells in acute myeloid leukemia. , 2015, Leukemia research.

[19]  Yu Cao,et al.  Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing , 2014, Science.

[20]  D. Dill,et al.  MYC through miR-17-92 suppresses specific target genes to maintain survival, autonomous proliferation, and a neoplastic state. , 2014, Cancer cell.

[21]  K. Patel,et al.  Identification of clinically important chromosomal aberrations in acute myeloid leukemia by array-based comparative genomic hybridization , 2014, Leukemia & lymphoma.

[22]  S. Robson,et al.  Recurrent mutations, including NPM1c, activate a BRD4-dependent core transcriptional program in acute myeloid leukemia , 2013, Leukemia.

[23]  R. Fanin,et al.  BAALC overexpression retains its negative prognostic role across all cytogenetic risk groups in acute myeloid leukemia patients , 2013, American journal of hematology.

[24]  T. Naoe,et al.  The demarcation between younger and older acute myeloid leukemia patients: A pooled analysis of 3 prospective studies , 2013, Cancer.

[25]  C. Bloomfield,et al.  New recurrent balanced translocations in acute myeloid leukemia and myelodysplastic syndromes: Cancer and leukemia group B 8461 , 2013, Genes, chromosomes & cancer.

[26]  J. León,et al.  MYC oncogene in myeloid neoplasias , 2013, Clinical and Translational Oncology.

[27]  D. Weisdorf,et al.  Survival for older patients with acute myeloid leukemia: a population-based study , 2012, Haematologica.

[28]  L. Staudt,et al.  Concurrent expression of MYC and BCL2 in diffuse large B-cell lymphoma treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone. , 2012, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  M. Konopleva,et al.  Clofarabine plus low‐dose cytarabine followed by clofarabine plus low‐dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients , 2012, Cancer.

[30]  Chi V Dang,et al.  MYC on the Path to Cancer , 2012, Cell.

[31]  B. Lüscher,et al.  Regulation of gene transcription by the oncoprotein MYC. , 2012, Gene.

[32]  H. Erba Has there been progress in the treatment of older patients with acute myeloid leukemia? , 2010, Best practice & research. Clinical haematology.

[33]  J. Dick,et al.  Comprehensive genomic screens identify a role for PLZF-RARalpha as a positive regulator of cell proliferation via direct regulation of c-MYC. , 2009, Blood.

[34]  R. Eisenman,et al.  Myc's broad reach. , 2008, Genes & development.

[35]  Kyu-Tae Kim,et al.  FLT3/ITD expression increases expansion, survival and entry into cell cycle of human haematopoietic stem/progenitor cells , 2007, British journal of haematology.

[36]  N. Young,et al.  CD34 cells from patients with trisomy 8 myelodysplastic syndrome (MDS) express early apoptotic markers but avoid programmed cell death by up-regulation of antiapoptotic proteins. , 2006, Blood.

[37]  A. W. Harris,et al.  MYC levels govern hematopoietic tumor type and latency in transgenic mice. , 2006, Blood.

[38]  Gerhard Ehninger,et al.  Prevalence and prognostic impact of NPM1 mutations in 1485 adult patients with acute myeloid leukemia (AML). , 2006, Blood.

[39]  H. Gundacker,et al.  Age and acute myeloid leukemia. , 2006, Blood.

[40]  E. Estey General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia. , 2006, Seminars in hematology.

[41]  W. Hiddemann,et al.  Nucleophosmin gene mutations are predictors of favorable prognosis in acute myelogenous leukemia with a normal karyotype. , 2005, Blood.

[42]  Stefan Fröhling,et al.  Mutant nucleophosmin (NPM1) predicts favorable prognosis in younger adults with acute myeloid leukemia and normal cytogenetics: interaction with other gene mutations. , 2005, Blood.

[43]  D. Gilliland,et al.  Drug therapy for acute myeloid leukemia. , 2005, Blood.

[44]  Paola Fazi,et al.  Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. , 2005, The New England journal of medicine.

[45]  D. Rimm,et al.  X-Tile , 2004, Clinical Cancer Research.

[46]  M. Wigler,et al.  Circular binary segmentation for the analysis of array-based DNA copy number data. , 2004, Biostatistics.

[47]  Ping Ji,et al.  Translocation Products in Acute Myeloid Leukemia Activate the Wnt Signaling Pathway in Hematopoietic Cells , 2004, Molecular and Cellular Biology.

[48]  A. Sánchez-Aguilera,et al.  Cell cycle deregulation in B-cell lymphomas. , 2003, Blood.

[49]  M. Keating,et al.  Higher levels of surface CD20 expression on circulating lymphocytes compared with bone marrow and lymph nodes in B-cell chronic lymphocytic leukemia. , 2001, American journal of clinical pathology.

[50]  R. Clark,et al.  Attempts to improve treatment outcomes in acute myeloid leukemia (AML) in older patients: the results of the United Kingdom Medical Research Council AML11 trial. , 2001, Blood.

[51]  W. Hiddemann,et al.  Management of acute myeloid leukemia in elderly patients. , 1999, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[52]  E. Prochownik,et al.  Deregulated expression of c-myc by murine erythroleukaemia cells prevents differentiation , 1986, Nature.

[53]  E. Dmitrovsky,et al.  Expression of a transfected human c-myconcogene inhibits differentiation of a mouse erythroleukaemia cell line , 1986, Nature.

[54]  M. Cole,et al.  Constitutive c-myc oncogene expression blocks mouse erythroleukaemia cell differentiation but not commitment , 1986, Nature.

[55]  David R. Cox,et al.  Regression models and life tables (with discussion , 1972 .

[56]  E. Kaplan,et al.  Nonparametric Estimation from Incomplete Observations , 1958 .