Disease relevance of MKL1

• A novel real-time RT-PCR assay for quantification of OTT-MAL fusion transcript reliable for diagnosis of t(1;22) and minimal residual disease (MRD) detection [1].
• Among children, besides the well-known Down syndrome M7, we in particular, studied ten t(1;22) M7 and one OTT-MAL transcript positive case with normal karyotype presenting specific features [2].
• The two most common hematologic neoplasms seen in this syndrome were acute megakaryoblastic leukemia and malignant histiocytosis [3].
• No such effect was seen when normal peripheral blood lymphocytes, lymphocytes from patients with chronic lymphatic leukemia, or blast cells from patients with B-cell acute lymphoblastic leukemia, acute erythroid leukemia, and acute megakaryoblastic leukemia were treated with neuraminidase [4].
• To date, we have obtained blood and/or tissue samples from 55 individuals consisting of 17 cases with TL, 7 cases of acute nonlymphocytic leukemia subtype M7 (ANLL-M7, or acute megakaryoblastic leukemia, postulated to be related to TL), and 31 cases of other forms of leukemia [5].
• Collectively, these functional and spatial changes of OTT and BSAC caused by the fusion might perturb their functions, culminating in the development of acute megakaryoblastic leukemia [6].

Psychiatry related information on MKL1

• Outcome measures included the Motor Activity Log for very low functioning patients (Grade 5 MAL), upper extremity portion of the Fugl-Meyer Motor Assessment, Graded Wolf Motor Function Test - for very low functioning patients (gWMFT- Grade 5), and Modified Ashworth Scale [7].

High impact information on MKL1

• Acquired somatic mutations in exon 2 of the hematopoietic transcription factor GATA-1 have been found in individuals with Down syndrome with both transient myeloproliferative disorder and acute megakaryoblastic leukemia [8].
• Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome [9].
• Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia [10].
• An article in the May 2 issue of Cell identifies the transcription factor MAL as an actin binding protein that functions as an SRF coactivator and whose translocation from cytoplasm to nucleus depends on its dissociation from actin monomers (Miralles et al., 2003) [11].
• Mediastinal germ cell tumor and acute megakaryoblastic leukemia [12].
• MAL appears to be centrally involved in promoting cancer cell invasion [13] and metastasis in experimental model systems [14]

Chemical compound and disease context of MKL1

• We have generated mice from a N-ethyl-N-nitrosourea mutagenesis screen that carry a mutation in the translation initiation codon of Gata-1, termed Plt13, which is equivalent to mutations found in patients with acute megakaryoblastic leukemia and Down syndrome [15].
• All of these "lymphoid" leukemias were TdT+, and 67% of evaluable patients had a complete response to V and P. One leukemia had the phenotype of an erythroleukemia, one patient's cells expressed the phenotype of megakaryoblastic leukemia, and one leukemia had populations of both myeloid and lymphoid blasts [16].
• Synthetic vitamin E, dl-alpha-tocopherol, added to a human erythroleukemia HEL and a megakaryoblastic leukemia, Meg-01, cell culture produced potent dose-dependent inhibition of phorbol ester-induced adhesion and of the morphologic changes accompanying it [17].
• Acute megakaryoblastic leukemia (FABM7) is an unusual but well recognized form of acute myelogenous leukemia in which the bone marrow blast cells are phenotypically recognized by the demonstration of cytoplasmic platelet peroxidase or surface staining for the IIb/IIIa platelet-specific glycoprotein [18].
• Evaluation of a 10 {micro}g cefoxitin disc for the detection of methicillin resistance in Staphylococcus aureus by BSAC methodology [19].

Biological context of MKL1

• We found that DN-MKL1 and RNAi specifically blocked SRE-dependent reporter gene activation by serum and RhoA [20].
• Overexpression of MKL1 transactivates serum response factor (SRF)-dependent SMC-restricted transcriptional regulatory elements including the SM22alpha promoter, smooth muscle myosin heavy chain promoter/enhancer, and SM-alpha-actin promoter/enhancer in non-SMCs [21].
• The covalent attachment of SUMO-1 to MKL1 by gene fusion represses MKL1-dependent transcription in a complementary manner [22].
• Consistent with a role in muscle specific gene expression, myocardin is specifically expressed in cardiac and smooth muscle cells while MKL1 and 2 are broadly expressed [23].
• In particular, rapid serum inducible phosphorylation of MKL1 was observed [23].

Anatomical context of MKL1

• In NIH3T3 fibroblasts MKL1 localizes to the cytoplasm and translocates to the nucleus in response to serum stimulation, actin treadmilling, and RhoA signaling [21].
• Together, these data were consistent with a model wherein MKL1 transduces signals from the cytoskeleton to the nucleus in SMCs and regulates SRF-dependent SMC differentiation autonomously or in concert with myocardin [21].
• RBM15 and MKL1 mutational screening in megakaryoblastic leukemia cell lines and clinical samples [24].
• MKL1 expression was found in newborn rat cortical or hippocampal neurons in culture as well as in adult rat forebrain [25].
• Immunostaining demonstrated constitutive nuclear localization of MKL1 in the CA1 region of the hippocampus, in the deep layers of the neocortex, and in cultured neurons [25].

Associations of MKL1 with chemical compounds

• AP3, a MoAb reactive with platelet glycoprotein (GPIIIa), was specific for acute megakaryoblastic leukemia [26].
• dl-alpha-tocopherol, a potent inhibitor of phorbol ester induced shape change of erythro- and megakaryoblastic leukemia cells [17].
• Tentative MIC and zone diameter breakpoints were determined for moxifloxacin using BSAC criteria [27].
• Reply to: Ciprofloxacin susceptibility testing of enterococcal urinary isolates in accordance with BSAC guidelines [28].
• Totally, 81%, 79% and 89% of colistin-resistant isolates were falsely reported as susceptible when tested by the product insert, BSAC and SFM testing methods, respectively [29].

Regulatory relationships of MKL1

• The MKL1 gene is expressed in most human tissues and myocardin and MKL are co-expressed in SMCs [21].
• Overexpression of BSAC in DKO MEFs partially inhibited TNF-induced cell death by suppressing activation of caspases [30].
• In the former condition, blasts are always positive with CD34, while in acute megakaryoblastic leukemia they express CD34 in 60% of the cases [31].
• Functionally active thrombomodulin (TM) was expressed in human megakaryoblastic leukemia (MEG-01s) cells [32].
• On the other hand, one patient with acute megakaryoblastic leukemia transformed from refractory anemia had a poor prognosis with megakaryoblastic leukemia cells which expressed no PF4 mRNA [33].

Other interactions of MKL1

• It has been shown that MKL1 functions as a RhoA-regulated transcriptional coactivator of serum response factor (SRF) [22].
• Forced expression of a dominant-negative MKL1 mutant reduces myocardin-induced activation of the SMC-specific SM22alpha promoter [21].
• In contrast, in SMCs MKL1 is observed exclusively in the nucleus regardless of serum conditions or RhoA signaling [21].
• Parathyroid hormone-related protein, chromogranin A, and calcitonin gene products in the neuroendocrine skin carcinoma cell lines MKL1 and MKL2 [34].
• These results suggest that neuronal MKL1 contributes to SRF-regulated gene expression induced by BDNF or synaptic activity [25].

Analytical, diagnostic and therapeutic context of MKL1

• JAK2T875N is a novel activating mutation that results in myeloproliferative disease with features of megakaryoblastic leukemia in a murine bone marrow transplantation model [35].
• For this study, highly purified populations of MK were prepared from human bone marrow either by counterflow centrifugal elutriation or by cell culture from normal subjects and from two patients with megakaryoblastic leukemia [36].
• One patient was in her fourth relapse, one had relapsed acute megakaryoblastic leukemia (following remission with DAT and HD-Ara-C), one had a treatment-induced leukemia, and four patients were treated for primary treatment failures following two induction courses with DAT or a similar regimen [37].
• Diagnosis of acute megakaryoblastic leukemia by flow cytometry and immunoalkaline phosphatase techniques. Utilization of new monoclonal antibodies [38].
• Comments on the report of the BSAC working party (WP) on self-medication of antibacterials without prescription [39].

References