Myeloid Targeted Human MLL-ENL and MLL-AF9 Induces cdk9 and bcl2 Expression in Zebrafish Embryos.

Acute myeloid leukemia (AML) accounts for greater than twenty thousand new cases of leukemia annually in the United States. The average five-year survival rate is approximately 30%, pointing to the need for developing novel model systems for drug discovery. In particular, patients with chromosomal rearrangements in the mixed lineage leukemia (MLL) gene have higher relapse rates with poor outcomes.

Constitutively active CaMKII Drives B lineage acute lymphoblastic leukemia/lymphoma in tp53 mutant zebrafish.

Acute lymphoblastic leukemia/lymphoma (ALL) is the most common pediatric cancer and is a malignancy of T or B lineage lymphoblasts. Dysregulation of intracellular Ca2+ levels has been observed in patients with ALL, leading to improper activation of downstream signaling. Here we describe a new zebrafish model of B ALL, generated by expressing human constitutively active CaMKII (CA-CaMKII) in tp53 mutant lymphocytes.

Specific CaMKIIs mediate convergent extension cell movements in early zebrafish development.

Background: Noncanonical Wnts are morphogens that can elevate intracellular Ca, activate the Ca/calmodulin-dependent protein kinase, CaMKII, and promote cell movements during vertebrate gastrulation.

Results: Zebrafish express seven CaMKII genes during embryogenesis; two of these, camk2b1 and camk2g1, are necessary for convergent extension (CE) cell movements. CaMKII morphant phenotypes were observed as early as epiboly.

Genetic compensation of γ CaMKII, an evolutionarily conserved gene.

CaMKII is a Ca/CaM-dependent protein kinase encoded by a family of conserved genes found throughout all metazoan species and expressed from fertilization into adulthood. One of these genes, camk2g1, is particularly important during early development as determined by pharmacologic, dominant negative and antisense morpholino approaches in zebrafish. Four other teleost fish species (cavefish, medaka, stickleback, and tilapia), exhibit sequence conservation of camk2g1 and duplication of the same CaMKII genes.

Widespread Roles of CaMK-II in Developmental Pathways.

The multifunctional Ca/calmodulin-dependent protein kinase type 2 (CaMK-II) was first discovered in brain tissue and shown to have a central role in long term potentiation, responding to Ca elevations through voltage dependent channels. CaMK-II has a unique molecular mechanism that enables it to remain active in proportion to the degree (frequency and amplitude) of Ca elevations, long after such elevations have subsided. Ca is also a rapid activator of early development and CaMK-II is expressed and activated in early development.