Studies in mice indicate that the Mkl1 gene (only the first letter of a mouse gene is capitalized)  product, MKL1, interacts with the transcription factor SRF to stimulate the expression of various genes. MKLl is required for the maturation of mouse megakaryoblasts: in its absence, megakaryoblasts and promegakaryocytes proliferate abnormally while megakaryocytes are few in number and have an abnormal morphology. Mouse studies also indicate that the product of Rbm15, RMB15, interacts with Nuclear receptor co-repressor 1, Nuclear receptor co-repressor 2 (also termed SMRT), and RBPJ nuclear proteins to suppress the expression of various genes that are involved in the maturation of platelet, myeloid and lymphocyte precursor cells. In consequence, the RBM15-MKL1 fusion protein acts in an unregulated fashion to suppress MKL1 targeted genes while  stimulating RPBJ target genes. This causes an over-active Notch signaling pathway and, among other abnormalities, expansion of fetal hematopoiesis and development of AMKL in a small percentage of adult mice. It is assumed that these events must be accompanied by other, as yet undefined, oncogenic (i.e., cancer causing) events to explain the development of human non-Down AMKL. A large number of other genetic abnormalities are associated with the development of non-DS-AMLK. These include complex chromosomal rearrangements and increases in copy number of various genes. Besides the t(1;22)(p13;q13) translocation, common genetic abnormalities in a study of 372 individuals diagnosed with non-DS-AMKL include: rearrangements of genes at position 23 on the long (i.e.
q) arm of chromosome 11; inversion of chromosome 16 occurring between p13.3 and q24.3 denoted as inv(16)(p13.3q24.3) that results in the production of a CBFA2T3-GLIS2 fusion protein; and increases in chromosome numbers from a normal of 46 to anywhere from 47 to >50. The relationships of these and the many other genetic abnormalities detected in non-Down-AMKL to the diseases development require further investigations. Presentation
Non-DS-AMKL occurs in neonates, infants, and children of all ages. Except for the lack of Down syndrome, no history of TMD, and occurrences in children that can be >4 years of age, individuals with non-DS-AMKL present with many of the symptoms, signs, and hematological findings seen in DS-AMKL. However, non-DS-AMKL is a more aggressive and rapidly progressing disorder than DS-AMKL. Nonetheless, the presentation of non-DS-AMKL is also like DS-AMKL in that it is not often accompanied by one or more extramedullary signs or symptoms of the disease such as liver enlargement, spleen enlargement, leukemia cutis, and leukostasis. Diagnosis
The diagnosis of non-DS-AMKL is made in children who do not have Down syndrome but exhibit the same clinical symptoms, signs, hematological abnormalities, and specialized laboratory findings seen in DS-AMKL. These children should bear one or more of the genetic aberrations associated with the disease but not the inactivating GATA1 mutations, extra copies of chromosome 21 genes, or other genetic abnormalities associated with DS-AMKL.