Gene Summary

Gene:MYH11; myosin, heavy chain 11, smooth muscle
Aliases: AAT4, FAA4, SMHC, SMMHC
Summary:The protein encoded by this gene is a smooth muscle myosin belonging to the myosin heavy chain family. The gene product is a subunit of a hexameric protein that consists of two heavy chain subunits and two pairs of non-identical light chain subunits. It functions as a major contractile protein, converting chemical energy into mechanical energy through the hydrolysis of ATP. The gene encoding a human ortholog of rat NUDE1 is transcribed from the reverse strand of this gene, and its 3' end overlaps with that of the latter. The pericentric inversion of chromosome 16 [inv(16)(p13q22)] produces a chimeric transcript that encodes a protein consisting of the first 165 residues from the N terminus of core-binding factor beta in a fusion with the C-terminal portion of the smooth muscle myosin heavy chain. This chromosomal rearrangement is associated with acute myeloid leukemia of the M4Eo subtype. Alternative splicing generates isoforms that are differentially expressed, with ratios changing during muscle cell maturation. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
Databases:OMIM, VEGA, HGNC, Ensembl, GeneCard, Gene
Source:NCBIAccessed: 21 August, 2015


What does this gene/protein do?
Show (18)

Cancer Overview

Research Indicators

Publications Per Year (1990-2015)
Graph generated 21 August 2015 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

  • Wilms Tumour
  • Acute Myeloid Leukaemia
  • Messenger RNA
  • Molecular Sequence Data
  • Pericardium
  • Young Adult
  • Residual Disease
  • Neoplasm Proteins
  • Myeloid Leukemia
  • Chromosome 8
  • Mutation
  • Chromosome Aberrations
  • Infant
  • Remission Induction
  • Core Binding Factor Alpha 2 Subunit
  • Core Binding Factors
  • Leukaemia
  • Bone Marrow
  • Base Sequence
  • Transcription Factor RelA
  • Adolescents
  • Translational Medical Research
  • FISH
  • Cancer RNA
  • Chromosome Inversion
  • DNA-Binding Proteins
  • Childhood Cancer
  • Chromosome 16
  • Core Binding Factor beta Subunit
  • Gene Rearrangement
  • WT1
  • Karyotyping
  • Pathology, Molecular
  • Trisomy
  • Homologous Transplantat
  • Polymerase Chain Reaction
  • Sarcoma, Myeloid
  • Oncogene Fusion Proteins
  • Leukemia, Myelomonocytic, Acute
Tag cloud generated 21 August, 2015 using data from PubMed, MeSH and CancerIndex

Specific Cancers (5)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: MYH11 (cancer-related)

Illendula A, Pulikkan JA, Zong H, et al.
Chemical biology. A small-molecule inhibitor of the aberrant transcription factor CBFβ-SMMHC delays leukemia in mice.
Science. 2015; 347(6223):779-84 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is the most common form of adult leukemia. The transcription factor fusion CBFβ-SMMHC (core binding factor β and the smooth-muscle myosin heavy chain), expressed in AML with the chromosome inversion inv(16)(p13q22), outcompetes wild-type CBFβ for binding to the transcription factor RUNX1, deregulates RUNX1 activity in hematopoiesis, and induces AML. Current inv(16) AML treatment with nonselective cytotoxic chemotherapy results in a good initial response but limited long-term survival. Here, we report the development of a protein-protein interaction inhibitor, AI-10-49, that selectively binds to CBFβ-SMMHC and disrupts its binding to RUNX1. AI-10-49 restores RUNX1 transcriptional activity, displays favorable pharmacokinetics, and delays leukemia progression in mice. Treatment of primary inv(16) AML patient blasts with AI-10-49 triggers selective cell death. These data suggest that direct inhibition of the oncogenic CBFβ-SMMHC fusion protein may be an effective therapeutic approach for inv(16) AML, and they provide support for transcription factor targeted therapy in other cancers.

Hájková H, Fritz MH, Haškovec C, et al.
CBFB-MYH11 hypomethylation signature and PBX3 differential methylation revealed by targeted bisulfite sequencing in patients with acute myeloid leukemia.
J Hematol Oncol. 2014; 7:66 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Studying DNA methylation changes in the context of structural rearrangements and point mutations as well as gene expression changes enables the identification of genes that are important for disease onset and progression in different subtypes of acute myeloid leukemia (AML) patients. The aim of this study was to identify differentially methylated genes with potential impact on AML pathogenesis based on the correlation of methylation and expression data.
METHODS: The primary method of studying DNA methylation changes was targeted bisulfite sequencing capturing approximately 84 megabases (Mb) of the genome in 14 diagnostic AML patients and a healthy donors' CD34+ pool. Subsequently, selected DNA methylation changes were confirmed by 454 bisulfite pyrosequencing in a larger cohort of samples. Furthermore, we addressed gene expression by microarray profiling and correlated methylation of regions adjacent to transcription start sites with expression of corresponding genes.
RESULTS: Here, we report a novel hypomethylation pattern, specific to CBFB-MYH11 fusion resulting from inv(16) rearrangement that is associated with genes previously described as upregulated in inv(16) AML. We assume that this hypomethylation and corresponding overexpresion occurs in the genes whose function is important in inv(16) leukemogenesis. Further, by comparing all targeted methylation and microarray expression data, PBX3 differential methylation was found to correlate with its gene expression. PBX3 has been recently shown to be a key interaction partner of HOX genes during leukemogenesis and we revealed higher incidence of relapses in PBX3-overexpressing patients.
CONCLUSIONS: We discovered new genomic regions with aberrant DNA methylation that are associated with expression of genes involved in leukemogenesis. Our results demonstrate the potential of the targeted approach for DNA methylation studies to reveal new regulatory regions.

Wang RJ, Wu P, Cai GX, et al.
Down-regulated MYH11 expression correlates with poor prognosis in stage II and III colorectal cancer.
Asian Pac J Cancer Prev. 2014; 15(17):7223-8 [PubMed] Related Publications
The MYH11 gene may be related to cell migration and adhesion, intracellular transport, and signal transduction. However, its relationship with prognosis is still uncertain. The aim of this study was to investigate correlations between MYH11 gene expression and prognosis in 58 patients with stage II and III colorectal cancer. Quantitative real-time polymerase chain reaction was performed in fresh CRC tissues to examine mRNA expression, and immunohistochemistry was performed with paraffin-embedded specimens for protein expression. On univariate analysis, MYH11 expression at both mRNA and protein levels, perineural invasion and lymphovascular invasion were related to disease-free survival (p<0.05; log-rank test). Cancers with lower MYH11 expression were more likely to have a poor prognosis. Otherwise, MYH11 expression was unrelated to patient clinicopathological features. On multivariate analysis, low MYH11 expression proved to be an independent adverse prognosticator (p<0.05). These findings show that MYH11 can contribute to predicting prognosis in stage II and III colorectal cancers.

Hayashi N, Manyam GC, Gonzalez-Angulo AM, et al.
Reverse-phase protein array for prediction of patients at low risk of developing bone metastasis from breast cancer.
Oncologist. 2014; 19(9):909-14 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A biomarker that predicts bone metastasis based on a protein laboratory assay has not been demonstrated. Reverse-phase protein array (RPPA) enables quantification of total and phosphorylated proteins, providing information about their functional status. The aim of this study was to identify bone-metastasis-related markers in patients with primary breast cancer using RPPA analysis.
PATIENTS AND METHODS: Tumor samples were obtained from 169 patients with primary invasive breast carcinoma who underwent surgery. The patients were categorized by whether they developed breast cancer bone metastasis (BCBM) during follow-up. Clinical characteristics and protein expression by RPPA were compared and verified by leave-one-out cross-validation.
RESULTS: Lymph node status (p = .023) and expression level of 22 proteins by RPPA were significantly correlated with BCBM in logistic regression analysis. These variables were used to build a logistic regression model. After filtering the variables through a stepwise algorithm, the final model, consisting of 8 proteins and lymph node status, had sensitivity of 30.0%, specificity of 90.5%, positive predictive value of 30.0%, and negative predictive value of 90.5% in the cross-validation. Most of the identified proteins were associated with cell cycle or signal transduction (CDK2, CDKN1A, Rb1, Src, phosphorylated-ribosomal S6 kinase, HER2, BCL11A, and MYH11).
CONCLUSION: Our validated model, in which the primary tumor is tested with RPPA, can predict patients who are at low risk of developing BCBM and thus who likely would not benefit from receiving a bisphosphonate in the adjuvant setting. Clinical trials excluding these patients have the potential to clarify the benefit of bisphosphonates in the adjuvant setting.

Lopez-Camacho C, van Wijnen AJ, Lian JB, et al.
CBFβ and the leukemogenic fusion protein CBFβ-SMMHC associate with mitotic chromosomes to epigenetically regulate ribosomal genes.
J Cell Biochem. 2014; 115(12):2155-64 [PubMed] Free Access to Full Article Related Publications
Mitotic bookmarking is an epigenetic control mechanism that sustains gene expression in progeny cells; it is often found in genes related to the maintenance of cellular phenotype and growth control. RUNX transcription factors regulate a broad spectrum of RNA Polymerase (Pol II) transcribed genes important for lineage commitment but also regulate RNA Polymerase I (Pol I) driven ribosomal gene expression, thus coordinating control of cellular identity and proliferation. In this study, using fluorescence microscopy and biochemical approaches we show that the principal RUNX co-factor, CBFβ, associates with nucleolar organizing regions (NORs) during mitosis to negatively regulate RUNX-dependent ribosomal gene expression. Of clinical relevance, we establish for the first time that the leukemogenic fusion protein CBFβ-SMMHC (smooth muscle myosin heavy chain) also associates with ribosomal genes in interphase chromatin and mitotic chromosomes to promote and epigenetically sustain regulation of ribosomal genes through RUNX factor interactions. Our results demonstrate that CBFβ contributes to the transcriptional regulation of ribosomal gene expression and provide further understanding of the epigenetic role of CBFβ-SMMHC in proliferation and maintenance of the leukemic phenotype.

Kihara R, Nagata Y, Kiyoi H, et al.
Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients.
Leukemia. 2014; 28(8):1586-95 [PubMed] Related Publications
To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics.

Al-Kzayer LF, Uyen le TN, Al-Jadiry MF, et al.
Analysis of class I and II aberrations in Iraqi childhood acute myeloid leukemia using filter paper cards.
Ann Hematol. 2014; 93(6):949-55 [PubMed] Related Publications
The lack of molecular diagnosis in the field of cancer in Iraq has motivated us to perform a genetic analysis of pediatric acute myelogenous leukemia (AML), including class I and II aberrations. Peripheral blood or bone marrow cells were collected from 134 AML children aged ≤15 years. Flinders Technology Associates (FTA) filter paper cards were used to transfer dried blood samples from five Iraqi hospitals to Japan. DNA sequencing was performed to identify class I mutations. Nested RT-PCR was used to detect class II aberrations, except that MLL rearrangement was detected according to long distance inverse-PCR. NPM1 and FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations were analyzed by GeneScan using DNA template. Among 134 Iraqi pediatric AML samples, the most prevalent FAB subtype was M2 (33.6 %) followed by M3 (17.9 %). Class I mutations: 20 (14.9 %), 8 (6.0 %), and 8 (6.0 %) patients had FLT3-ITD, FLT3-TKD, and KIT mutations, respectively. Class II mutations: 24 (17.9 %), 19 (14.2 %), and 9 (6.7 %) children had PML-RARA, RUNX1-RUNX1T1, and CBFB-MYH11 transcripts, respectively. MLL rearrangements were detected in 25 (18.7 %) patients. NPM1 mutation was detected in seven (5.2 %) cases. Collectively, approximately 30 % of AML children were proved to carry favorable prognostic genetic abnormalities, whereas approximately 10 % had high FLT3-ITD allelic burden and needed a special treatment plan including allogeneic hematopoietic stem cell transplantation. Acute promyelocytic leukemia (APL) was frequent among Iraqi pediatric AML. It is likely that molecular diagnosis using FTA cards in underdeveloped countries could guide doctors towards an appropriate treatment strategy.

Albano F, Anelli L, Zagaria A, et al.
Acute myeloid leukemia with t(16;16) (p13;q22) showing a new CBFB-MYH11 fusion transcript associated with an atypical leukemic blasts morphology.
Hum Pathol. 2014; 45(3):643-7 [PubMed] Related Publications
Acute myeloid leukemia (AML) cases with inv(16)(p13q22) or t(16;16)(p13;q22) are characterized by multiple CBFB-MYH11 fusion transcripts, type A being the most frequent. Rare fusion variants are frequently correlated with an atypical cytomorphology, but their biologic and prognostic significance is unclear. We report a case of acute myeloid leukemia with a balanced t(16;16)(p13;q22) and additional monosomy 13 showing a new CBFB-MYH11 fusion transcript variant. The patient also showed an atypical morphology of bone marrow blasts, since about 15% of all blasts showed bilobed nuclei but there was no pathologic eosinophilia. The biologic and prognostic implications of this rare association are discussed.

Fortunato A, Gasparoli L, Falsini S, et al.
An analytical method for the quantification of hERG1 channel gene expression in human colorectal cancer.
Diagn Mol Pathol. 2013; 22(4):215-21 [PubMed] Related Publications
Cancer molecular investigation revealed a huge molecular heterogeneity between different types of cancers as well as among cancer patients affected by the same cancer type. This implies the necessity of a personalized approach for cancer diagnosis and therapy, on the basis of the development of standardized protocols to facilitate the application of molecular techniques in the clinical decision-making process. Ion channels encoding genes are acquiring increasing relevance in oncological translational studies, representing new candidates for molecular diagnostic and therapeutic purposes. Hence, the development of molecular protocols for the quantification of ion channels encoding genes in tumor specimens may have relevance for diagnostic and prognostic investigation. Two main hindrances must be overcome for these purposes: the use of formalin-fixed and paraffin-embedded samples for gene expression analysis and the physiological expression of ion channels in excitable cells, potentially present in the tumor sample. We here propose a method for hERG1 gene quantification in colorectal cancer samples in both cryopreserved and formalin-fixed and paraffin-embedded samples. An analytical method was developed to estimate hERG1 gene expression exclusively in epithelial cancer cells. Indeed, we found that the hERG1 gene was expressed at significant levels by myofibroblasts present in the tumor stroma. This method was based on the normalization on a smooth muscle-myofibroblast-specific gene, MYH11, with no need of microdissection. By applying this method, hERG1 expression turned out to correlate with VEGF-A expression, confirming previous immunohistochemical data.

Ben-Ami O, Friedman D, Leshkowitz D, et al.
Addiction of t(8;21) and inv(16) acute myeloid leukemia to native RUNX1.
Cell Rep. 2013; 4(6):1131-43 [PubMed] Related Publications
The t(8;21) and inv(16) chromosomal aberrations generate the oncoproteins AML1-ETO (A-E) and CBFβ-SMMHC (C-S). The role of these oncoproteins in acute myeloid leukemia (AML) etiology has been well studied. Conversely, the function of native RUNX1 in promoting A-E- and C-S-mediated leukemias has remained elusive. We show that wild-type RUNX1 is required for the survival of t(8;21)-Kasumi-1 and inv(16)-ME-1 leukemic cells. RUNX1 knockdown in Kasumi-1 cells (Kasumi-1(RX1-KD)) attenuates the cell-cycle mitotic checkpoint, leading to apoptosis, whereas knockdown of A-E in Kasumi-1(RX1-KD) rescues these cells. Mechanistically, a delicate RUNX1/A-E balance involving competition for common genomic sites that regulate RUNX1/A-E targets sustains the malignant cell phenotype. The broad medical significance of this leukemic cell addiction to native RUNX1 is underscored by clinical data showing that an active RUNX1 allele is usually preserved in both t(8;21) or inv(16) AML patients, whereas RUNX1 is frequently inactivated in other forms of leukemia. Thus, RUNX1 and its mitotic control targets are potential candidates for new therapeutic approaches.

Mandoli A, Singh AA, Jansen PW, et al.
CBFB-MYH11/RUNX1 together with a compendium of hematopoietic regulators, chromatin modifiers and basal transcription factors occupies self-renewal genes in inv(16) acute myeloid leukemia.
Leukemia. 2014; 28(4):770-8 [PubMed] Related Publications
Different mechanisms for CBFβ-MYH11 function in acute myeloid leukemia with inv(16) have been proposed such as tethering of RUNX1 outside the nucleus, interference with transcription factor complex assembly and recruitment of histone deacetylases, all resulting in transcriptional repression of RUNX1 target genes. Here, through genome-wide CBFβ-MYH11-binding site analysis and quantitative interaction proteomics, we found that CBFβ-MYH11 localizes to RUNX1 occupied promoters, where it interacts with TAL1, FLI1 and TBP-associated factors (TAFs) in the context of the hematopoietic transcription factors ERG, GATA2 and PU.1/SPI1 and the coregulators EP300 and HDAC1. Transcriptional analysis revealed that upon fusion protein knockdown, a small subset of the CBFβ-MYH11 target genes show increased expression, confirming a role in transcriptional repression. However, the majority of CBFβ-MYH11 target genes, including genes implicated in hematopoietic stem cell self-renewal such as ID1, LMO1 and JAG1, are actively transcribed and repressed upon fusion protein knockdown. Together these results suggest an essential role for CBFβ-MYH11 in regulating the expression of genes involved in maintaining a stem cell phenotype.

Mir Mazloumi SH, Appaji L, Madhumathi DS, Prasannakumari
G-banding and fluorescence in situ hybridization in childhood acute myeloid leukemia from South India.
Arch Iran Med. 2013; 16(8):459-62 [PubMed] Related Publications
BACKGROUND: The current WHO classification of hematologic malignancies defines distinct entities of myeloid disorders based on the presence of recurrent cytogenetic abnormalities. Diagnostic clonal chromosomal abnormalities provide important prognostic information and are among the most important factors in predicting initial response to chemotherapy, duration of remission and overall survival. 
METHODS: This study analyzed chromosomal abnormalities in bone marrow aspirates of 50 children diagnosed with acute myeloid leuckemia (AML). 
RESULTS: The culture success rate was 94%, clonal chromosomal abnormalities constituted 62% and recurrent chromosomal abnormalities were 56%. In the favorable prognostic category, there were 51.6% of cases with t(8;21)(q22;q22), 16.1% had t(15;17)(q22;q21), and a total of 12.9% had chromosome 16 rearrangement. The adverse risk category showed a low frequency of t(9;11)(p22;q13); t(1;22)(p13;q13); inv(3)( q21q26); add 4(q35) and ring chromosome. According to fluorescent in situ hybridization (FISH) results in 16 cytogenetically normal patients, there were no CBFβ/MYH11 fusion genes observed in chromosome 16 rearrangements. 
DISCUSSION: Larger studies of this kind may provide more information about chromosome 16 rearrangements in cytogenetically normal patients. The present analysis suggests that both age and cytogenetics are important strategies for risk stratification (outcome). Additional laboratory parameters should also be considered in childhood AML.

Opatz S, Polzer H, Herold T, et al.
Exome sequencing identifies recurring FLT3 N676K mutations in core-binding factor leukemia.
Blood. 2013; 122(10):1761-9 [PubMed] Related Publications
The t(8;21) and inv(16)/t(16;16) rearrangements affecting the core-binding factors RUNX1 and CBFB, respectively, are found in 15% to 20% of adult de novo acute myeloid leukemia (AML) cases and are associated with a favorable prognosis. Since the expression of the fusion genes CBFB/MYH11 or RUNX1/RUNX1T1 alone is not sufficient to cause leukemia, we performed exome sequencing of an AML sample with an inv(16) to identify mutations, which may collaborate with the CBFB/MYH11 fusion during leukemogenesis. We discovered an N676K mutation in the adenosine triphosphate (ATP)-binding domain (tyrosine kinase domain 1 [TKD1]) of the fms-related tyrosine kinase 3 (FLT3) gene. In a cohort of 84 de novo AML patients with a CBFB/MYH11 rearrangement and in 36 patients with a RUNX1/RUNX1T1 rearrangement, the FLT3 N676K mutation was identified in 5 and 1 patients, respectively (5 [6%] of 84; 1 [3%] of 36). The FLT3-N676K mutant alone leads to factor-independent growth in Ba/F3 cells and, together with a concurrent FLT3-ITD (internal tandem duplication), confers resistance to the FLT3 protein tyrosine kinase inhibitors (PTKIs) PKC412 and AC220. Gene expression analysis of AML patients with CBFB/MYH11 rearrangement and FLT3 N676K mutation showed a trend toward a specific expression profile. Ours is the first report of recurring FLT3 N676 mutations in core-binding factor (CBF) leukemias and suggests a defined subgroup of CBF leukemias.

Yoon JH, Kim HJ, Shin SH, et al.
BAALC and WT1 expressions from diagnosis to hematopoietic stem cell transplantation: consecutive monitoring in adult patients with core-binding-factor-positive AML.
Eur J Haematol. 2013; 91(2):112-21 [PubMed] Related Publications
No consecutive analysis of BAALC and WT1 expressions associated with core-binding factor AML (CBF-AML) from diagnosis to hematopoietic stem cell transplantation (HSCT) has yet been reported. We investigated BAALC and WT1 expressions using a method of real-time quantitative polymerase chain reaction (RQ-PCR) at diagnosis, after induction chemotherapy, at pre-HSCT, and at post-HSCT period in 45 consecutive patients [t(8,21) (n = 28), inv(16) (n = 17)], who received HSCT as a post-remission treatment. BAALC and WT1 RQ-PCR decrement ratio (DR) was also calculated at post-induction chemotherapy, at pre-HSCT, and at post-HSCT compared with the diagnostic level. Higher BAALC expression at diagnosis showed significantly inferior OS (P = 0.031), EFS (P = 0.011), and higher CIR (P = 0.002) rates. At post-HSCT, both higher BAALC and WT1 expressions showed significantly inferior OS (P = 0.005, 0.016), EFS (P = 0.002, 0.006), and higher CIR (P = 0.001, 0.003) rates. A subgroup of t(8;21) showing higher BAALC and WT1 expressions at post-HSCT were also associated with inferior OS (P = 0.018, 0.015) and higher CIR rates (P = 0.019, 0.011). While BAALC DR showed no significant results on outcomes, WT1 DR more than 2-log at post-HSCT showed significantly lower CIR rate (P = 0.028). This study showed that higher post-HSCT BAALC and WT1 expressions in patients with CBF-AML may be good markers of minimal residual disease for the prediction of survival and relapse after HSCT.

Hoyos M, Nomdedeu JF, Esteve J, et al.
Core binding factor acute myeloid leukemia: the impact of age, leukocyte count, molecular findings, and minimal residual disease.
Eur J Haematol. 2013; 91(3):209-18 [PubMed] Related Publications
PURPOSE: Most patients with acute myeloid leukemia (AML) and genetic rearrangements involving the core binding factor (CBF) have favorable prognosis. In contrast, a minority of them still have a high risk of leukemia recurrence. This study investigated the adverse features of CBF AML that could justify investigational therapeutic approaches.
PATIENTS AND METHODS: One hundred and fifty patients (median age 42 yr, range 16-69) with CBF AML (RUNX1-RUNX1T1 n = 74; CBFB-MYH11 n = 76) were prospectively enrolled into two consecutive CETLAM protocols at 19 Spanish institutions. Main clinic and biologic parameters were analyzed in the whole series. In non-selected cases with available DNA samples, the impact of molecular characterization and minimal residual disease (MRD) was also studied.
RESULTS: Overall, complete remission (CR) rate was 89% (94% in ≤50 yr old and 72% in >50 yr, P = 0.002). At 5 yr, cumulative incidence of relapse (CIR) was 26 ± 1%, disease-free survival (DFS) 62 ± 6%, and overall survival (OS) 66 ± 4%. In multivariate analyses, leukocyte count above 20 × 10(9) /L, BAALC over-expression, and high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy (CT) led to increased relapse rate. Regarding OS, age >50 yr, leukocyte count above 20 × 10(9) /L, and increased MN1 expression were adverse features.
CONCLUSION: Age, leukocyte counts, BAALC, and MN1 gene expressions as well as high copy numbers of RUNX1-RUNXT1 or CBFB-MYH11 after induction chemotherapy are useful tools to predict the outcome and should be considered for risk-adapted therapy.

Costa AR, Vasudevan A, Krepischi A, et al.
Single-nucleotide polymorphism-array improves detection rate of genomic alterations in core-binding factor leukemia.
Med Oncol. 2013; 30(2):579 [PubMed] Related Publications
Acute myeloid leukemia (AML) is a group of clonal diseases, resulting from two classes of mutation. Investigation for additional abnormalities associated with a well-recognized subtype, core-binding factor AML (CBF-AML) can provide further understanding and discrimination to this special group of leukemia. In order to better define genetic alterations in CBF-AML and identify possible cooperating lesions, a single-nucleotide polymorphism-array (SNP-array) analysis was performed, combined to KIT mutation screening, in a set of cases. Validation of SNP-array results was done by array comparative genomic hybridization and FISH. Fifteen cases were analyzed. Three cases had microscopic lesions better delineated by arrays. One case had +22 not identified by arrays. Submicroscopic abnormalities were mostly non-recurrent between samples. Of relevance, four regions were more frequently affected: 4q28, 9p11, 16q22.1, and 16q23. One case had an uncovered unbalanced inv(16) due to submicroscopic deletion of 5´MYH11 and 3´CBFB. Telomeric and large copy number neutral loss of heterozygosity (CNN-LOH) regions (>25 Mb), likely representing uniparental disomy, were detected in four out of fifteen cases. Only three cases had mutation on KIT gene, enhancing the role of abnormalities by SNP-array as presumptive cooperating alterations. Molecular karyotyping can add valuable information to metaphase karyotype analysis, emerging as an important tool to uncover and characterize microscopic, submicroscopic genomic alterations, and CNN-LOH events in the search for cooperating lesions.

Schwind S, Edwards CG, Nicolet D, et al.
inv(16)/t(16;16) acute myeloid leukemia with non-type A CBFB-MYH11 fusions associate with distinct clinical and genetic features and lack KIT mutations.
Blood. 2013; 121(2):385-91 [PubMed] Free Access to Full Article Related Publications
The inv(16)(p13q22)/t(16;16)(p13;q22) in acute myeloid leukemia results in multiple CBFB-MYH11 fusion transcripts, with type A being most frequent. The biologic and prognostic implications of different fusions are unclear. We analyzed CBFB-MYH11 fusion types in 208 inv(16)/t(16;16) patients with de novo disease, and compared clinical and cytogenetic features and the KIT mutation status between type A (n = 182; 87%) and non-type A (n = 26; 13%) patients. At diagnosis, non-type A patients had lower white blood counts (P = .007), and more often trisomies of chromosomes 8 (P = .01) and 21 (P < .001) and less often trisomy 22 (P = .02). No patient with non-type A fusion carried a KIT mutation, whereas 27% of type A patients did (P = .002). Among the latter, KIT mutations conferred adverse prognosis; clinical outcomes of non-type A and type A patients with wild-type KIT were similar. We also derived a fusion-type-associated global gene-expression profile. Gene Ontology analysis of the differentially expressed genes revealed-among others-an enrichment of up-regulated genes involved in activation of caspase activity, cell differentiation and cell cycle control in non-type A patients. We conclude that non-type A fusions associate with distinct clinical and genetic features, including lack of KIT mutations, and a unique gene-expression profile.

Kamikubo Y, Hyde RK, Zhao L, et al.
The C-terminus of CBFβ-SMMHC is required to induce embryonic hematopoietic defects and leukemogenesis.
Blood. 2013; 121(4):638-42 [PubMed] Free Access to Full Article Related Publications
The C-terminus of CBFβ-SMMHC, the fusion protein produced by a chromosome 16 inversion in acute myeloid leukemia subtype M4Eo, contains domains for self-multimerization and transcriptional repression, both of which have been proposed to be important for leukemogenesis by CBFβ-SMMHC. To test the role of the fusion protein's C-terminus in vivo, we generated knock-in mice expressing a C-terminally truncated CBFβ-SMMHC (CBFβ-SMMHCΔC95). Embryos with a single copy of CBFβ-SMMHCΔC95 were viable and showed no defects in hematopoiesis, whereas embryos homozygous for the CBFβ-SMMHCΔC95 allele had hematopoietic defects and died in mid-gestation, similar to embryos with a single-copy of the full-length CBFβ-SMMHC. Importantly, unlike mice expressing full-length CBFβ-SMMHC, none of the mice expressing CBFβ-SMMHCΔC95 developed leukemia, even after treatment with a mutagen, although some of the older mice developed a nontransplantable myeloproliferative disease. Our data indicate that the CBFβ-SMMHC's C-terminus is essential to induce embryonic hematopoietic defects and leukemogenesis.

Paschka P, Du J, Schlenk RF, et al.
Secondary genetic lesions in acute myeloid leukemia with inv(16) or t(16;16): a study of the German-Austrian AML Study Group (AMLSG).
Blood. 2013; 121(1):170-7 [PubMed] Related Publications
In this study, we evaluated the impact of secondary genetic lesions in acute myeloid leukemia (AML) with inv(16)(p13.1q22) or t(16;16)(p13.1;q22); CBFB-MYH11. We studied 176 patients, all enrolled on prospective treatment trials, for secondary chromosomal aberrations and mutations in N-/KRAS, KIT, FLT3, and JAK2 (V617F) genes. Most frequent chromosomal aberrations were trisomy 22 (18%) and trisomy 8 (16%). Overall, 84% of patients harbored at least 1 gene mutation, with RAS being affected in 53% (45% NRAS; 13% KRAS) of the cases, followed by KIT (37%) and FLT3 (17%; FLT3-TKD [14%], FLT3-ITD [5%]). None of the secondary genetic lesions influenced achievement of complete remission. In multivariable analyses, KIT mutation (hazard ratio [HR] = 1.67; P = .04], log(10)(WBC) (HR = 1.33; P = .02), and trisomy 22 (HR = 0.54; P = .08) were relevant factors for relapse-free survival; for overall survival, FLT3 mutation (HR = 2.56; P = .006), trisomy 22 (HR = 0.45; P = .07), trisomy 8 (HR = 2.26; P = .02), age (difference of 10 years, HR = 1.46; P = .01), and therapy-related AML (HR = 2.13; P = .14) revealed as prognostic factors. The adverse effects of KIT and FLT3 mutations were mainly attributed to exon 8 and tyrosine kinase domain mutations, respectively. Our large study emphasizes the impact of both secondary chromosomal aberrations as well as gene mutations for outcome in AML with inv(16)/t (16;16).

Kanagal-Shamanna R, Zhao W, Vadhan-Raj S, et al.
Over-expression of CYP2E1 mRNA and protein: implications of xenobiotic induced damage in patients with de novo acute myeloid leukemia with inv(16)(p13.1q22); CBFβ-MYH11.
Int J Environ Res Public Health. 2012; 9(8):2788-800 [PubMed] Free Access to Full Article Related Publications
Environmental exposure to benzene occurs through cigarette smoke, unleaded gasoline and certain types of plastic. Benzene is converted to hematotoxic metabolites by the hepatic phase-I enzyme CYP2E1, and these metabolites are detoxified by the phase-II enzyme NQO1. The genes encoding these enzymes are highly polymorphic and studies of these polymorphisms have shown different pathogenic and prognostic features in various hematological malignancies. The potential role of different cytochrome p450 metabolizing enzymes in the pathogenesis of acute myeloid leukemia (AML) in an area of active interest. In this study, we demonstrate aberrant CYP2E1 mRNA over-expression by quantitative real-time polymerase chain reaction in 11 cases of de novo AML with inv(16); CBFβ-MYH11. CYP2E1 mRNA levels correlated with CBFβ-MYH11 transcript levels and with bone marrow blast counts in all cases. CYP2E1 over-expression correlated positively with NQO1 mRNA levels (R(2) = 0.934, n = 7). By immunohistochemistry, CYP2E1 protein was more frequently expressed in AML with inv(16) compared with other types of AML (p < 0.001). We obtained serial bone marrow samples from two patients with AML with inv(16) before and after treatment. CYP2E1 mRNA expression levels decreased in parallel with CBFβ-MYH11 transcript levels and blast counts following chemotherapy. In contrast, CYP1A2 transcript levels did not change in either patient. This is the first study to demonstrate concurrent over-expression of CYP2E1 and NQO1 mRNA in AML with inv(16). These findings also suggest that a balance between CYP2E1 and NQO1 may be important in the pathogenesis of AML with inv(16).

Li L, Li J, Li G, et al.
A tetraploid minimally differentiated acute myeloblastic leukemia with extensive erythrophagocytosis: a case report and literature review.
Int J Hematol. 2012; 96(6):801-5 [PubMed] Related Publications
Tetraploidy is a rare chromosome number aberration in de novo acute myeloid leukemia (AML), and may be associated with erythrophagocytosis by leukemic blast cells. We report a 48-year-old female patient with minimally differentiated acute myeloblastic leukemia (AML-M0) exhibiting tetraploidy and erythrophagocytosis. The karyotype was 46,XX[2]/92,XXXX[18]. Bone marrow aspirate smears showed large and prominent nuclei, with erythrophagocytosis in leukemic cells. Fluorescence in situ hybridization using RUNX1 dual color break probes detected four fusion signals, accounting for 95 % (190/200), in one interphase nucleus. The mutations of TP53 and the fusion genes RUNX1/ETO, CBFβ/MYH11, and PML/RARα were all negative. This patient showed a poor response to chemotherapy, and died 66 days after the onset. To our knowledge, this is the first reported case of AML-M0 with tetraploidy and erythrophagocytosis and without additional chromosome aberrations. This case of tetraploid AML with poor prognosis suggests that further biological study of more cases of tetraploid AML will be of great importance in improving the understanding and prognosis of this tetraploid AML.

Kim HJ, Ahn HK, Jung CW, et al.
KIT D816 mutation associates with adverse outcomes in core binding factor acute myeloid leukemia, especially in the subgroup with RUNX1/RUNX1T1 rearrangement.
Ann Hematol. 2013; 92(2):163-71 [PubMed] Related Publications
Core binding factor (CBF)-positive acute myeloid leukemia (AML) presents a favorable prognosis, except for patients with KIT mutation, especially D816 mutation. The current retrospective study attempted to validate a prognostic role of KIT mutation in 121 Korean patients with CBF AML. The study patients consisted of 121 patients with CBF AML (82 patients with RUNX1/RUNX1T1 [67.8 %] and 39 patients with CBFB/MYH11 [32.2 %]) recruited from eight institutions in Korea. All patients received idarubicin plus cytarabine or behenoyl cytosine arabinoside 3 + 7 induction chemotherapy. The KIT gene mutation status was determined by direct sequencing analyses. A KIT mutation was detected in 32 cases (26.4 %) in our series of patients. The KIT mutation was most frequent in exon 17 (n = 18, 14.9 %; n = 16 with D816 mutation), followed by exon 8 (n = 10, 8.3 %). The presence of KIT D816 mutation was associated with adverse outcomes for the event-free survival (p = 0.03) and for the overall survival (p = 0.02). The unfavorable impact of D816 mutation was more prominent when the analysis was confined to the RUNX1/RUNX1T1 subtype. The KIT mutation was detected in 26.4 % of Korean patients with CBF AML. The KIT D816 mutation demonstrated an unfavorable prognostic implication, particularly in the RUNX1/RUNX1T1 subtype.

Cunningham L, Finckbeiner S, Hyde RK, et al.
Identification of benzodiazepine Ro5-3335 as an inhibitor of CBF leukemia through quantitative high throughput screen against RUNX1-CBFβ interaction.
Proc Natl Acad Sci U S A. 2012; 109(36):14592-7 [PubMed] Free Access to Full Article Related Publications
Core binding factor (CBF) leukemias, those with translocations or inversions that affect transcription factor genes RUNX1 or CBFB, account for ~24% of adult acute myeloid leukemia (AML) and 25% of pediatric acute lymphocytic leukemia (ALL). Current treatments for CBF leukemias are associated with significant morbidity and mortality, with a 5-y survival rate of ~50%. We hypothesize that the interaction between RUNX1 and CBFβ is critical for CBF leukemia and can be targeted for drug development. We developed high-throughput AlphaScreen and time-resolved fluorescence resonance energy transfer (TR-FRET) methods to quantify the RUNX1-CBFβ interaction and screen a library collection of 243,398 compounds. Ro5-3335, a benzodiazepine identified from the screen, was able to interact with RUNX1 and CBFβ directly, repress RUNX1/CBFB-dependent transactivation in reporter assays, and repress runx1-dependent hematopoiesis in zebrafish embryos. Ro5-3335 preferentially killed human CBF leukemia cell lines, rescued preleukemic phenotype in a RUNX1-ETO transgenic zebrafish, and reduced leukemia burden in a mouse CBFB-MYH11 leukemia model. Our data thus confirmed that RUNX1-CBFβ interaction can be targeted for leukemia treatment and we have identified a promising lead compound for this purpose.

Geng Z, Zhang H, Wang D, et al.
Combination of cytogenetic analysis and molecular screening in patients with de novo acute myeloid leukemia.
J Huazhong Univ Sci Technolog Med Sci. 2012; 32(4):501-10 [PubMed] Related Publications
Nowadays the role of genetic findings in determining the diagnosis, therapy and prognosis of acute myeloid leukemia (AML) has become more valuable. To improve and validate the detection of clonal chromosomal aberrations in leukemia, we designed a combined application of karyotyping with multiplex reverse transcription-polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH), and addressed the expression and distribution of fusion genes among the subtypes of Chinese adult patients with de novo AML. Multiplex RT-PCR assays were performed on 477 samples from newly diagnosed AML patients, and cytogenetic data were obtained from 373 of them by R or G banding techniques and those in some cases were confirmed by FISH. The PCR products in some suspected cases were tested by two-directional sequencing. The results showed that except unqualified samples, fusion genes were detected by multiplex RT-PCR in 211 of 474 patients (44.51%), including AML1-ETO, CBFβ-MYH11, PML-RARα, PLZF-RARα, NPM-RARα, MLL rearrangements, BCR-ABL, DEK-CAN, SET-CAN, TEL-PDGFR, TLS-ERG, AML1-MDS1 (EVI-1). In 373 patients, who took both multiplex RT-PCR and karyotype analysis, the detection rate of chromosomal aberrations by using multiplex RT-PCR and karyotyping was 160/373 (42.89%) and 179/373 (47.98%) respectively, and the combination could optimize the detection rate of clonal genetic abnormalities to 216/373 (57.90%). The PCR results from 11 cases "normal" in karyotyping but abnormal in RT-PCR for MLL rearrangements were confirmed by two-directional sequencing. It is concluded that karyotype studies remain the cornerstone for genetic testing; conventional cytogenetics and molecular-based methods are complementary tests for the detection of clonal genetic aberrations in AML, especially for the cryptic or submicroscopic aberrations. Once a genetic marker has been identified by combined analysis, it could be used to monitor residual disease during/after chemotherapy, by quantitative RT-PCR and/or FISH.

Eghtedar A, Borthakur G, Ravandi F, et al.
Characteristics of translocation (16;16)(p13;q22) acute myeloid leukemia.
Am J Hematol. 2012; 87(3):317-8 [PubMed] Free Access to Full Article Related Publications
A subgroup of patients with core binding factor acute myeloid leukemias (AML) is characterized by the presence of the fusion gene CBFb-Myh11. At the cytogenetic level, most of these patients are identified by the presence of an inversion of chromosome 16 [inv(16)(p13q22)] and rarely by a translocation t(16;16)(p13;q22). The aim of this study is to describe the natural history of patients with t(16;16) [N = 6] treated at MD Anderson Cancer Center and compared them with a cohort of patients with inv(16)(p13q22) [n = 61]. In patients with t(16;16) the complete remission rate (CR) was 100% when treated with a combination of fludarabine and high-dose cytarabine. Median overall survival (OS) had not been achieved. There was no difference in response or OS or progression free survival between both groups. Presence of additional chromosomal abnormalities and molecular aberrations had no effect on prognosis. In conclusion, and consistent with previous reports, the natural history of patients with t(16:16)(p13;q22) is similar to that of classic patients with inv16 AML and therefore should be treated similarly.

Zhao L, Melenhorst JJ, Alemu L, et al.
KIT with D816 mutations cooperates with CBFB-MYH11 for leukemogenesis in mice.
Blood. 2012; 119(6):1511-21 [PubMed] Free Access to Full Article Related Publications
KIT mutations are the most common secondary mutations in inv(16) acute myeloid leukemia (AML) patients and are associated with poor prognosis. It is therefore important to verify that KIT mutations cooperate with CBFB-MYH11, the fusion gene generated by inv(16), for leukemogenesis. Here, we transduced wild-type and conditional Cbfb-MYH11 knockin (KI) mouse bone marrow (BM) cells with KIT D816V/Y mutations. KIT transduction caused massive BM Lin(-) cell death and fewer colonies in culture that were less severe in the KI cells. D816Y KIT but not wild-type KIT enhanced proliferation in Lin(-) cells and led to more mixed lineage colonies from transduced KI BM cells. Importantly, 60% and 80% of mice transplanted with KI BM cells expressing D816V or D816Y KIT, respectively, died from leukemia within 9 months, whereas no control mice died. Results from limiting dilution transplantations indicate higher frequencies of leukemia-initiating cells in the leukemia expressing mutated KIT. Signaling pathway analysis revealed that p44/42 MAPK and Stat3, but not AKT and Stat5, were strongly phosphorylated in the leukemia cells. Finally, leukemia cells carrying KIT D816 mutations were sensitive to the kinase inhibitor PKC412. Our data provide clear evidence for cooperation between mutated KIT and CBFB-MYH11 during leukemogenesis.

Kristensen T, Preiss B, Broesby-Olsen S, et al.
Systemic mastocytosis is uncommon in KIT D816V mutation positive core-binding factor acute myeloid leukemia.
Leuk Lymphoma. 2012; 53(7):1338-44 [PubMed] Related Publications
The KIT D816V mutation is detected in the vast majority of adult cases of systemic mastocytosis (SM). The mutation is also frequently detected in core-binding factor acute myeloid leukemia (CBF AML) defined by the presence of t(8;21)(q22;q22); RUNX1-RUNX1T1 or inv(16)(p13.1;q22)/t(16;16)(p13.1;q22); CBFB-MYH11 chromosomal rearrangements, but whether the mutation is indicative of associated SM is unclear. In the present study, patients with CBF AML were therefore analyzed for the KIT D816V mutation and mutation positive cases subsequently analyzed for the presence of SM. The KIT D816V mutation was detected in eight of 20 cases of CBF AML, with the frequency in t(8;21)(q22;q22) and inv(16)(p13.1;q22) positive cases being 31% and 57%, respectively. The fraction of KIT D816V mutation positive cells was highly variable among the eight mutation positive patients, with levels ranging from 0.04 to 98% in a pretreatment blood sample. Five of the eight cases carried the mutation in a cell fraction below one-tenth of the blast cell fraction, thus suggesting that KIT mutation is often a late event in leukemogenesis. None of the eight KIT D816V mutation positive cases fulfilled the World Health Organization diagnostic criteria of SM. The presence of the KIT D816V mutation in the CBF AML subgroup can therefore not be considered indicative of associated SM.

Roychowdhury S, Iyer MK, Robinson DR, et al.
Personalized oncology through integrative high-throughput sequencing: a pilot study.
Sci Transl Med. 2011; 3(111):111ra121 [PubMed] Free Access to Full Article Related Publications
Individual cancers harbor a set of genetic aberrations that can be informative for identifying rational therapies currently available or in clinical trials. We implemented a pilot study to explore the practical challenges of applying high-throughput sequencing in clinical oncology. We enrolled patients with advanced or refractory cancer who were eligible for clinical trials. For each patient, we performed whole-genome sequencing of the tumor, targeted whole-exome sequencing of tumor and normal DNA, and transcriptome sequencing (RNA-Seq) of the tumor to identify potentially informative mutations in a clinically relevant time frame of 3 to 4 weeks. With this approach, we detected several classes of cancer mutations including structural rearrangements, copy number alterations, point mutations, and gene expression alterations. A multidisciplinary Sequencing Tumor Board (STB) deliberated on the clinical interpretation of the sequencing results obtained. We tested our sequencing strategy on human prostate cancer xenografts. Next, we enrolled two patients into the clinical protocol and were able to review the results at our STB within 24 days of biopsy. The first patient had metastatic colorectal cancer in which we identified somatic point mutations in NRAS, TP53, AURKA, FAS, and MYH11, plus amplification and overexpression of cyclin-dependent kinase 8 (CDK8). The second patient had malignant melanoma, in which we identified a somatic point mutation in HRAS and a structural rearrangement affecting CDKN2C. The STB identified the CDK8 amplification and Ras mutation as providing a rationale for clinical trials with CDK inhibitors or MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) and PI3K (phosphatidylinositol 3-kinase) inhibitors, respectively. Integrative high-throughput sequencing of patients with advanced cancer generates a comprehensive, individual mutational landscape to facilitate biomarker-driven clinical trials in oncology.

Sangle NA, Perkins SL
Core-binding factor acute myeloid leukemia.
Arch Pathol Lab Med. 2011; 135(11):1504-9 [PubMed] Related Publications
Core-binding factor acute myeloid leukemia (AML) is cytogenetically defined by the presence of t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22), commonly abbreviated as t(8;21) and inv(16), respectively. In both subtypes, the cytogenetic rearrangements disrupt genes that encode subunits of core-binding factor, a transcription factor that functions as an essential regulator of normal hematopoiesis. The rearrangements t(8;21) and inv(16) involve the RUNX1/RUNX1T1 ( AML1-ETO ) and CBFB/MYH11 genes, respectively. These 2 subtypes are categorized as AML with recurrent genetic abnormalities, and hence the cytogenetic fusion transcripts are considered diagnostic of acute leukemia even when the marrow blast count is less than 20%. The t(8;21) and inv(16) subtypes of AML have been usually grouped and reported together in clinical studies; however, recent studies have demonstrated genetic, clinical, and prognostic differences, supporting the notion that they represent 2 distinct biologic and clinical entities. This review summarizes the spectrum of this subset of AMLs, with particular emphasis on molecular genetics and pathologic findings.

Shen Y, Zhu YM, Fan X, et al.
Gene mutation patterns and their prognostic impact in a cohort of 1185 patients with acute myeloid leukemia.
Blood. 2011; 118(20):5593-603 [PubMed] Related Publications
To evaluate the prognostic value of genetic mutations for acute myeloid leukemia (AML) patients, we examined the gene status for both fusion products such as AML1 (CBFα)-ETO, CBFβ-MYH11, PML-RARα, and MLL rearrangement as a result of chromosomal translocations and mutations in genes including FLT3, C-KIT, N-RAS, NPM1, CEBPA, WT1, ASXL1, DNMT3A, MLL, IDH1, IDH2, and TET2 in 1185 AML patients. Clinical analysis was mainly carried out among 605 cases without recognizable karyotype abnormalities except for 11q23. Of these 605 patients, 452 (74.7%) were found to have at least 1 mutation, and the relationship of gene mutations with clinical outcome was investigated. We revealed a correlation pattern among NPM1, DNMT3A, FLT3, IDH1, IDH2, CEBPA, and TET2 mutations. Multivariate analysis identified DNMT3A and MLL mutations as independent factors predicting inferior overall survival (OS) and event-free survival (EFS), whereas biallelic CEBPA mutations or NPM1 mutations without DNMT3A mutations conferred a better OS and EFS in both the whole group and among younger patients < 60 years of age. The use of molecular markers allowed us to subdivide the series of 605 patients into distinct prognostic groups with potential clinical relevance.

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