[Blocking PAK1 kinase activity promotes the differentiation of acute megakaryocytic leukemia cells and induces their apoptosis].

Objective: To investigate the effect of blocking P21 activated kinase 1 (PAK1) activity on the proliferation, differentiation, and apoptosis of acute megakaryocytic leukemia (AMKL) cell lines (CHRF and CMK) . Methods: Cell counts were used to detect the effects of PAK1 inhibitors (IPA-3 and G5555) on AMKL cell proliferation inhibition and colony formation, and flow cytometry was used to detect its effects on AMKL cell cycle. The effect of PAK1 inhibitor on the expression of cyclin D1 and apoptosis-related protein Cleaved caspase 3 was detected using Western blot, while interference with the protein expression level of PAK1 in AMKL cells was assessed using lentivirus-mediated shRNA transfection technology. Flow cytometry was used to detect the effects of knockdown of PAK1 kinase activity on the ability of polyploid DNA formation and cell apoptosis in AMKL cells. Results: PAK1 inhibitors inhibited the proliferation of AMKL cells in a dose-dependent manner and reduced the ability of cell colony formation, and the difference was statistically significant when compared with the control group (P<0.05) . Moreover, they also reduced the percentage of AMKL cells in S phase, and Western blot detection showed that the expression levels of phosphorylated PAK1 and cyclin D1 decreased significantly. Finally, PAK1 inhibitors induced AMKL cell apoptosis by up-regulating Cleaved caspase 3 and showed different abilities to increase the content of polyploid DNA in megakaryocytes. Only high concentrations of IPA-3 and low doses of G5555 increased the number of polyploid megakaryocytes, while knockdown of PAK1 kinase activity promoted AMKL cell differentiation and increased the apoptosis rate. Conclusion: PAK1 inhibitor significantly arrests AMKL cell growth and promotes cell apoptosis. Knocking down the expression of PAK1 promotes the formation of polyploid DNA and induces AMKL cell apoptosis. The above findings indicate that inhibiting the activity of PAK1 may control AMKL effectively.

Breast ductal carcinoma in situ with micro-invasion versus ductal carcinoma in situ: a comparative analysis of clinicopathological and mammographic findings.

AIM: To determine the differences in clinicopathological and mammographic findings between ductal carcinoma in situ (DCIS) and ductal carcinoma in situ with micro-invasion (DCIS-MI) and explore clinicopathological and mammographic factors associated with DCIS-MI. MATERIALS AND METHODS: All DCIS patients with or without micro-invasion who underwent preoperative mammography at The Affiliated Hospital of Qingdao University from January 2016 through June 2020 were identified retrospectively. The correlations of clinicopathological findings with DCIS-MI were evaluated using univariate and multivariate binary logistic regression analyses. Imaging findings were compared between the groups by using the Pearson chi-square test. RESULTS: A total of 445 DCIS lesions and 151 DCIS-MI lesions were included in the final analysis. Large extent (≥2.7 cm), high nuclear grade, comedo-type, negative progesterone receptor (PR), negative oestrogen receptor (ER), high Ki-67 and axillary lymph node metastasis were more frequently found in DCIS-MI than in DCIS (all p<0.05), and the first four of these were found to be independent predictors of DCIS-MI in the multivariate analysis (all p<0.05). Regarding imaging findings, compared to DCIS, DCIS-MI showed fewer occult lesions and more lesions with calcifications in mass, asymmetry, and architectural distortion (p=0.004). Grouped calcifications were usually associated with DCIS, while regional calcifications were commonly found in DCIS-MI (p<0.05). CONCLUSION: Large extent, high nuclear grade, comedo-type and negative PR were found to be independent predictors of DCIS-MI. Lesions with calcifications and regional calcifications were more likely associated with DCIS-MI on mammography.

[Expression of HMGB1 protein in breast cancer and its clinicopathological significance].

Objective: To investigate the expression and clinicopathological significance of high mobility group box protein B1 (HMGB1) protein in breast cancer. Methods: The expression of HMGB1 protein in 26 normal breast tissues and 417 invasive breast cancer tissues diagnosed at Dongyang People's Hospital, Zhejiang Province from 2016 to 2018 were detected by immunohistochemical EnVision method. The relationship between nuclear and cytoplasmic HMGB1 protein expression and clinicopathologic features of breast cancer patients were analyzed. Results: The nuclear and cytoplasmic expression of HMGB1 protein was 80.8% (337/417) and 16.8% (70/417) respectively in breast cancer, and was 46.2%(12/26) and 0(0/26) respectively in normal breast tissue. Both nuclear and cytoplasmic expression of HMGB1 protein in breast cancer were significantly higher than normal breast tissue (P<0.001, P=0.046, respectively). The nuclear expression of HMGB1 protein was also higher in high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative (P=0.006, P=0.004, P<0.001, respectively); whereas the cytoplasmic expression of HMGB1 protein was also higher in high grade, estrogen receptor (ER) negative, progesterone receptor (PR) negative (P<0.001 in all) breast cancers. Multivariate logistic regression model showed that nuclear HMGB1 expression correlated with histologic grade (OR=2.188, 95%CI=1.078-4.443, P=0.030), while cytoplasmic HMGB1 expression correlated with histologic grade (OR=3.031, 95%CI=1.600-5.742, P=0.001), ER (OR=0.129, 95%CI=0.034-0.494, P=0.003) and TNM staging (OR=3.820, 95%CI=1.042-14.001, P=0.043). Multivariate analysis of Cox proportional hazard model showed that nuclear HMGB1 expression was an independent risk factor for the overall survival of breast cancer patients (HR=0.366, 95%CI=0.138-0.972, P=0.044). Conclusion: Nuclear and cytoplasmic HMGB1 proteins are related to multiple poor prognostic factors in breast cancer, and may be a potential biomarker for breast cancer treatment.

MiR-181a affects myocardial ischemia-reperfusion injury in rats via regulating akt signaling pathway.

OBJECTIVE: The aim of this study was to explore the influence of the micro ribonucleic acid (miR)-181a on myocardial ischemia-reperfusion injury (MIRI) in rats by regulating the protein kinase B (Akt) signaling pathway. MATERIALS AND METHODS: A total of 30 male Sprague-Dawley rats were randomly divided into three groups, including: sham operation group (Sham group), ischemia-reperfusion group (I/R group), and miR group (MiR-181a group). The model of myocardial ischemia-reperfusion was successfully established in rats. The concentration of blood nitric oxide (NO) was detected by the relative kits. Myocardial apoptosis in rats of the three groups was detected using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. Furthermore, the expressions of myocardial cell apoptosis-related proteins and tumor necrosis factor-α (TNF-α), and the degree of Akt phosphorylation were determined by Western blotting. RESULTS: Compared with Sham group and miR-181a group, I/R group exhibited significantly elevated left ventricular end-diastolic pressure (LVEDP) (p<0.05). However, the left ventricular end-systolic pressure (LVESP), stroke work (SW), differential pressure (DP), end-systolic pressure-volume relationship (ESPVR), and end-diastolic pressure-volume relationship (EDPVR) significantly decreased in the I/R group (p<0.05). In comparison with miR-181a group, the apoptosis index of myocardial cells was remarkably elevated in the I/R group, showing statistically significant differences (p<0.05). The protein bands were analyzed using the Quantity One detection software. The results demonstrated that, compared with the Sham group, I/R group showed significantly elevated expressions of cysteine-aspartic protease (Caspase)-3 and TNF-α in rat myocardial tissues (p<0.05). However, the protein levels of Akt and endothelial NO synthase (eNOS) phosphorylation and NO in rat myocardial cells were significantly down-regulated (p<0.05). CONCLUSIONS: MiR-181a activates Akt to promote the phosphorylation of its downstream protein eNOS, inhibit the apoptosis of myocardial cells, and alleviate MIRI.

Role and mechanism of microRNA-548c-3p/c-Myb in myocardial infarction fibrosis in rats.

OBJECTIVE: To investigate the role of micro ribonucleic acid (miR)-548c-3p in myocardial fibrosis after myocardial infarction (MI), and to explore the possible underlying. MATERIALS AND METHODS: The rat model of MI was successfully established in-vivo. MiR-548c-3p was upregulated via lentivirus transfection with miR-548c-3p mimics. Cardiac function of rats was detected via echocardiography. Meanwhile, Sirius red and Masson staining were used to detect the level of fibrosis index in MI model. Subsequently, myocardial fibroblasts were isolated and cultured in vitro. An oxygen-glucose deprivation (OGD) model was established to mimicking the ischemic condition. Furthermore, the relationship between miR-548c-3p and c-Myb was verified, and the levels of fibrosis-related factors (including α-SMA and COL1A1) were measured. RESULTS: In-vivo experiments showed that miR-548c-3p expression in rats was significantly down-regulated at 2 and 4 weeks after MI. Up-regulation of miR-548c-3p significantly improved cardiac function, reduced myocardial fibrosis and inhibited the protein expression of proto-oncogene c-Myb (c-Myb). In vitro experiments revealed that c-Myb was a target gene of miR-548c-3p. In addition, miR-548c-3p could inhibit the expressions of α-SMA and COL1A1 through targeting c-Myb. CONCLUSIONS: MiR-548c-3p could improve myocardial fibrosis by targeting c-Myb.

MiR-195 reverses 5-FU resistance through targeting HMGA1 in gastric cancer cells.

OBJECTIVE: To investigate the role of micro ribonucleic acid (miR)-195 in acquired resistance to 5-fluorouracil (5-FU) in gastric cancer and its potential mechanism. MATERIALS AND METHODS: The drug resistance of AGS/5-FU and SGC-7901/5-FU cells compared with their parental cells was verified via methyl thiazolyl tetrazolium (MTT) assay, and the expression levels of miR-195 and high-mobility group protein A1 (HMGA1) in AGS/5-FU and SGC-7901/5-FU cells were detected via quantitative Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) and Western blotting. MiR-195 mimic and miR-195 inhibitor were transfected into AGS/5-FU and AGS cells, respectively, the changes in HMGA1 expression were detected via qRT-PCR and Western blotting, and the sensitivity of cells to 5-FU after transfection was detected via MTT assay. After the wild-type and mutant-type luciferase reporter plasmids of HMGA1 were co-transfected with miR-195 mimic or miR-195 NC into cells, the luciferase activity was analyzed using the dual-luciferase reporter system. Finally, the rescue experiment was performed to confirm whether the changes in HMGA1 expression promote the formation of drug resistance in gastric cancer. RESULTS: Both AGS/5-FU and SGC-7901/5-FU cells were significantly resistant to 5-FU compared with their parental cells, and miR-195 was down-regulated in AGS/5-FU and SGC-7901/5-FU cells, while HMGA1 was up-regulated in AGS and SGC-7901 cells. The transfection with miR-195 mimic could suppress the expression level of HMGA1 in AGS/5-FU cells, while the transfection with miR-195 inhibitor could up-regulate the expression level of HMGA1 in AGS cells. Moreover, miR-195 could bind to HMGA1 3'-untranslated region (3'UTR) in a targeted way, thereby inhibiting its expression. It was confirmed via a rescue experiment that the changes in HMGA1 expression promoted the formation of drug resistance in gastric cancer. CONCLUSIONS: The down-regulation of miR-195 induces the resistance to 5-FU in gastric cancer through promoting the expression of HMGA1.

[The correlations between distance stereoacuity and levels of control at different far distances in children with intermittent exotropia].

Objective: To study the correlations between the distance stereoacuity and the levels of control at different far distance fixations in children with intermittent exotropia. Methods: In this prospective, non-interventional case series study, 52 children with intermittent exotropia (basic, divergence excess and pseudo-divergence excess types, exodeviation angles≥15 PD) admitted to the Shandong Provincial Hospital Affiliated to Shandong University for surgery between August 2014 and March 2015 were enrolled. The distance stereoacuity was tested with the distance Randot stereotest, and the control of exodeviation was assessed at outdoor far distance fixation of 50 m, indoor far distance fixation of 30 m, and indoor distance fixation of 3 m, respectively, using the office-based 6-point control scale proposed by Mohney and Holmes. The distance stereoacuity and control scores of every intermittent exotropia child were tested 3-4 times in a single day with an interval of at least 2 hours. Nonparametric Spearman rank method was used to analyze the correlations between distance stereoacuity and levels of control at three different far distances in children with intermittent exotropia. Results: The mean age of 52 enrolled children (26 males, 26 females) was 7 years (range, 5-12 years), and 192 groups of distance stereoacuity and control scores were got for the 52 children. Positive correlations between the distance stereoacuity and the levels of control at outdoor far distance fixation of 50 m, indoor far distance fixation of 30 m, and indoor distance fixation of 3 m were observed (coefficients of correlations; r=0.489, 0.472, 0.282, all P<0.001). Conclusion: There are correlations between the distance stereoacuity and the levels of control at outdoor far distance fixation of 50 m, indoor far distance fixation of 30 m and indoor distance fixation of 3 m in children with intermittent exotropia, and the former two are found to be stronger than the latter one. (Chin J Ophthalmol, 2019, 55:25-30).

[Nasalleukoplakia：update on diagnosis and management].

Nasal leukoplakia, defined as nasal mucosal grayish white lesion accompanied by adjacent mucosa thickening and hyperemia, is a kind of precancerous lesion. Since a case of nasal septum mucosal leukoplakia reported by Edley in 1955 and 62 cases of nasal leukoplakia reported by Liu Chun-Lin in 1964, few cases were reported. In this review, the pathogenesis, diagnosis and treatment of nasal mucosal leukoplakia are systematically summarized. Attention should be paid to this disease to reduce the possibility of incidence of malignant tumors.

Effects of forkhead Box protein A1 on cell proliferation regulating and EMT of cervical carcinoma.

OBJECTIVE: Cervical cancer is a common tumor in gynecological malignancies. However, the patients are often in an advanced stage when diagnosed. It was found that forkhead box protein A1 (FOXA1) is abnormally expressed in various tumors, such as breast cancer, ovarian cancer, and is closely related to tumorigenesis. This study aimed to investigate the expression and the related roles of FOXA1 in cervical cancer. PATIENTS AND METHODS: Real Time-PCR (RT-PCR) and Western blot were used to analyze expression of FOXA1 in cervical cancer and adjacent tissue. The small-interfere RNA (siRNA) was adopted to down-regulate FOXA1 expression in HeLa cells. The effect of FOXA1 on apoptosis of HeLa cells was detected by using thiazolyl blue tetrazolium bromide (MTT) method. The apoptosis rate of HeLa cells was detected by using flow cytometry. The Western blot was selected to evaluate the epithelial mesenchymal transition (EMT) related protein, vimentin, E-cadherin, and vascular endothelial growth factor (VEGF) changes. RESULTS: Compared with adjacent tissues, FOXA1 mRNA and protein expressions significantly increased in cervical cancer (p<0.05). SiRNA significantly reduced FOXA1 expression in Hela cells compared with the control group and siRNA-NC group, thus inhibiting tumor cell proliferation and enhancing cell apoptosis rate (p<0.05). E-cadherin elevated, Vimentin decreased, and VEGF reduced after FOXA1 siRNA treatment. CONCLUSIONS: FOXA1 expression increased in cervical cancer. Inhibition of FOXA1 expression blocked the proliferation of cervical cancer, promoted tumor cell apoptosis, suppressed the occurrence of EMT and VEGF production, and can regulate cervical cancer metastasis. FOXA1 can be used as a new molecular biological target for cervical cancer diagnosis and treatment.

[Streptococcal toxic shock syndrome caused by Streptococcus pyogenes: a retrospective study of 15 pediatric cases].

Objective: To improve the understanding of clinical characteristics of streptococcal toxic shock syndrome (STSS) caused by Streptococcus pyogenes (S. pyogenes) in children. Methods: A retrospective study was conducted to analyze the clinical data of STSS caused by S. pyogenes (culture-confirmed) in 7 tertiary hospitals during 2010-2017 in China. Clinical and laboratory data were collected by reviewing the medical records. Results: Fifteen cases of STSS, including 9 males, were confirmed and the ages of the patients ranged from 6 months to 15 years, with median age of 3 years. All cases had the positive blood culture for S. pyogenes and only 3 cases had short course of ß-lactam treatment before blood culture. Medical evaluation was initiated within (5.1±4.6) days after symptom onset. All patients had fever, and 13 patients had multiple organ dysfunction and 10 patients had disseminated intravascular coagulationl (DIC). Twelve cases had severe pneumonia with or without skin and (or) soft tissue infections. Underlying conditions included giant hemangioma of the skin in 2 patients and varicella in 1 patient. All isolated strains in 14 cases were sensitive to penicillin G, ceftriaxone/cefotaxime, vancomycin, but 12 and 13 isolates were resistant to clindamycin and erythromycin, respectively. Eight patients died, and 5 of them died within 24 hours after admission. One patient was lost to follow-up after intended discharge against medical advice. Conclusion: STSS caused by S. pyogenes in children is a severe syndrome with rapid clinical progression and high mortality rate, and thus the pediatricians should be aware of STSS and immediately initiate aggressive treatment for the suspected cases.

MiR-377 suppresses cell proliferation and metastasis in gastric cancer via repressing the expression of VEGFA.

OBJECTIVE: In recent years, microRNAs have been identified to participate in tumor genesis and progression of different tumors including gastric cancer. However, the role of miR-377 played in gastric cancer (GC), and its mechanisms have not been demonstrated. PATIENTS AND METHODS: We detected miR-377 expression level in 86 GC and adjacent normal tissue samples by quantitative reverse transcription PCR (qRT-PCR) as well as in GC cell lines. The relationship between miR-377 and clinical pathological features was analyzed. Using miR-377 mimics and inhibitors, we interfered with miR-377 level and employed several functional experiments to study the miR-377 effects on cell proliferation, migration, and invasion. Western blot assay and dual-luciferase assay were used to verify the target of miR-377. RESULTS: miR-377 expressed significantly lower in GC tissues and cell lines compared to normal tissues and GES-1 cells. Overexpression of miR-377 inhibited cell growth, migration and invasion, while downregulation miR-377 obviously promoted cell growth and metastasis. Furthermore, vascular endothelial growth factor A (VEGFA) was confirmed as a direct target of miR-377 and reversed the influence of mir-377 over-expression. CONCLUSIONS: miR-377 expressed lower in GC and suppressed cell proliferation, migration and invasion partly via repressing the VEGFA expression, which could provide a potential target for GC diagnosis and therapy.

Aberrant activation of the GIMAP enhancer by oncogenic transcription factors in T-cell acute lymphoblastic leukemia.

The transcription factor TAL1/SCL is one of the most prevalent oncogenes in T-cell acute lymphoblastic leukemia (T-ALL), a malignant disorder resulting from leukemic transformation of thymus T-cell precursors. TAL1 is normally expressed in hematopoietic stem cells (HSCs) but is silenced in immature thymocytes. We hypothesize that TAL1 contributes to leukemogenesis by activating genes that are normally repressed in immature thymocytes. Herein, we identified a novel TAL1-regulated super-enhancer controlling the GIMAP locus, which resides within an insulated chromosomal locus in T-ALL cells. The GIMAP genes are expressed in HSCs and mature T cells but are downregulated during the immature stage of thymocyte differentiation. The GIMAP enhancer is activated by TAL1, RUNX1 and GATA3 in human T-ALL cells but is repressed by E-proteins. Overexpression of human GIMAP genes in immature thymocytes alone does not induce tumorigenesis but accelerates leukemia development in zebrafish. Our results demonstrate that aberrant activation of the GIMAP enhancer contributes to T-cell leukemogenesis.

Posttraumatic administration of a sub-anesthetic dose of ketamine exerts neuroprotection via attenuating inflammation and autophagy.

As a complex disease, traumatic brain injury (TBI) can result in long-term psychiatric changes and sensorimotor and cognitive impairments. The TBI-induced loss of memory and long-term cognitive dysfunction are related to mechanistic factors including an increased inflammatory response, autophagy, edema, and ischemia. Many published studies have offered evidence for the neuroprotective effects and anti-inflammatory properties of ketamine for TBI patients. Nonetheless, there is a limited understanding of the accurate mechanism that underlies the potential neuroprotective effects of ketamine. Herein, it can be shown that posttraumatic administration of ketamine at a sub-anesthetic dose (10mg/kg ketamine, every 24h up to 7days) can prevent the TBI-induced production of IL-6 and TNF-α, attenuate deficits of dendrites and spines and exert beneficial effects on memory and behavior. Moreover, studies show that ketamine may activate the mTOR signaling pathway by p-mTOR induction to down-regulate the expression of crucial autophagic proteins such as LC3 and Beclin-1. According to these findings, ameliorating secondary brain injury and anti-inflammatory properties is closely related to the neuroprotection of ketamine, which supports the use of ketamine as a potential therapy for patients with TBI to alleviate functional deficits.

[Identification and significance of myeloid-derived suppressor cells in peripheral blood of breast cancer patients].

OBJECTIVE: To investigate the presence, biological features, and clinical significance of myeloid-derived suppressor cells (MDSCs) in breast cancer patients. METHODS: Eighty-four cases of breast cancer, 37 cases of benign breast tumor and 21 cases of healthy individuals were included in this study. Samples of peripheral blood (2 ml) were collected, and in the breast cancer patients, blood samples were taken both before and after treatment. Flow cytometry using anti-CD11b, CD33, CD14 and HLA-DR antibody was conducted to identify the unique membrane markers of MDSCs, and statistical analysis was performed to explore the relationship between MDSCs and clinical factors. Cell isolation and in vitro assay were used to test T cell function. RESULTS: CD11b(+) CD33(+) CD14(-) MDSCs were present in the blood of breast cancer patients, and these MDSCs were histologically of mononuclear cells. Cell proliferation assay confirmed that MDSCs inhibited proliferation of homologous T cells in vitro. MDSCs levels in patients with breast cancer, benign disease and the health control were (15.93±3.17)%, (8.92±4.42)% and (5.02±2.75)%, respectively, with a statistically significant difference (P<0.001) between breast cancer patients and the other subjects (patients with benign lesions and healthy controls). The expression level of MDSCs in patients with breast cancer was associated with surgical treatment, but not with age, disease stage, lymph node metastasis, ER or PR expression. MDSCs levels were significantly lower in post-operative patients[(7.83±3.78) %] than the (15.37±2.49) % in patients before surgery (P<0.001). CONCLUSIONS: The results of this study demonstrate that MDSCs are present in the peripheral blood of breast cancer patients and the level of MDSCs is associated with surgical treatment. Our findings suggest that CD11b(+) CD33(+) CD14(-) MDSCs are likely involved in breast cancer initiation and development, and may become a novel biomarker to facilitate diagnosis and to predict clinical outcomes of breast cancer.

Mouse models for core binding factor leukemia.

RUNX1 and CBFB are among the most frequently mutated genes in human leukemias. Genetic alterations such as chromosomal translocations, copy number variations and point mutations have been widely reported to result in the malfunction of RUNX transcription factors. Leukemias arising from such alterations in RUNX family genes are collectively termed core binding factor (CBF) leukemias. Although adult CBF leukemias generally are considered a favorable risk group as compared with other forms of acute myeloid leukemia, the 5-year survival rate remains low. An improved understanding of the molecular mechanism for CBF leukemia is imperative to uncover novel treatment options. Over the years, retroviral transduction-transplantation assays and transgenic, knockin and knockout mouse models alone or in combination with mutagenesis have been used to study the roles of RUNX alterations in leukemogenesis. Although successful in inducing leukemia, the existing assays and models possess many inherent limitations. A CBF leukemia model which induces leukemia with complete penetrance and short latency would be ideal as a platform for drug discovery. Here, we summarize the currently available mouse models which have been utilized to study CBF leukemias, discuss the advantages and limitations of individual experimental systems, and propose suggestions for improvements of mouse models.

RUNX1 meets MLL: epigenetic regulation of hematopoiesis by two leukemia genes.

A broad range of human leukemias carries RUNX1 and MLL genetic alterations. Despite such widespread involvements, the relationship between RUNX1 and MLL has never been appreciated. Recently, we showed that RUNX1 physically and functionally interacts with MLL, thereby regulating the epigenetic status of critical cis-regulatory elements for hematopoietic genes. This newly unveiled interaction between the two most prevalent leukemia genes has solved a long-standing conundrum: leukemia-associated RUNX1 N-terminal point mutants that exhibit no obvious functional abnormalities in classical assays for the assessment of transcriptional activities. These mutants turned out to be defective in MLL interaction and subsequent epigenetic modifications that can be examined by the histone-modification status of cis-regulatory elements in the target genes. RUNX1/MLL binding confirms the importance of RUNX1 function as an epigenetic regulator. Recent studies employing next-generation sequencing on human hematological malignancies identified a plethora of mutations in epigenetic regulator genes. These new findings would enhance our understanding on the mechanistic basis for leukemia development and may provide a novel direction for therapeutic applications. This review summarizes the current knowledge about the epigenetic regulation of normal and malignant hematopoiesis by RUNX1 and MLL.