NKL-Code in Normal and Aberrant Hematopoiesis

Abstract

We have recently described physiological expression patterns of NKL homeobox genes in early hematopoiesis and in subsequent lymphopoiesis and myelopoiesis, including terminally differentiated blood cells. We thereby systematized differential expression patterns of eleven such genes which form the so-called NKL-code. Due to the developmental impact of NKL homeobox genes, these data suggest a key role for their activity in normal hematopoietic differentiation processes. On the other hand, the aberrant overexpression of NKL-code-members or the ectopical activation of non-code members have been frequently reported in lymphoid and myeloid leukemia/lymphoma, revealing the oncogenic potential of these genes in the hematopoietic compartment. Here, I provide an overview of the NKL-code in normal hematopoiesis and instance mechanisms of deregulation and oncogenic functions of selected NKL genes in hematologic cancers. As well as published clinical studies, our conclusions are based on experimental work using hematopoietic cell lines which represent useful models to characterize the role of NKL homeobox genes in specific tumor types.

NKL Homeobox Genes NKX2-3 and NKX2-4 Deregulate Megakaryocytic-Erythroid Cell Differentiation in AML

“…NKL homeobox genes are frequently deregulated by chromosomal aberrations [ 15 ]. To check if the NKX2-4 locus is targeted by chromosomal rearrangements, we performed karyotyping of OCI-M2.…”

“…In accordance with these published results, combined analysis of expression profiling data from normal hematopoietic cells and AML patient samples demonstrated physiological NKX2-3 activity in stem cells and aberrant expression in patients with KMT2A rearrangements and complex karyotypes ( Figure S4 ). In addition, NKX2-3 expression has been detected in myelodysplastic syndrome, diffuse large B-cell lymphoma, T-ALL, and T-cell lymphoma, showing its oncogenic potential in both myeloid and lymphoid cell lineages [ 15 ]. Increased colony forming and replating capacity after NKX2-3 overexpression has been shown in murine hematopoietic progenitor cells [ 42 ], supporting an impact in early differentiation processes.…”

“…Examples are NKX2-3 , which is expressed in developing spleen, intestine and in HSCs; NKX2-4 , which is active in brain and testis development; and NKX2-5 , which controls development of heart and spleen [ 10 , 11 , 12 , 13 , 14 ]. Recently, we have described the NKL-code that encompasses the gene signature of eleven NKL homeobox genes expressed in specific patterns during hematopoiesis [ 15 ]. Basic NKL-code members are NKX2-3 , in addition to both HHEX and HLX , which orchestrate differentiation processes in myeloid and lymphoid lineages and are themselves regulated by specific hematopoietic TFs [ 16 ].…”

“…For example, the ETS gene ETV6 is fused with different partner genes by specific translocations in lymphoblastic and myeloid acute leukemias, and NKL homeobox gene NKX2-5 is aberrantly activated via juxtaposition to an enhancer region of BCL11B in T-cell acute lymphoblastic leukemia (T-ALL) [ 17 , 18 ]. Other reported activating mechanisms for NKL homeobox genes are deregulated chromatin components, signaling pathways, and TFs [ 15 ]. Furthermore, aberrantly expressed ETS and NKL homeobox genes serve as diagnostic markers for certain hematopoietic cancers, such as ETV6 in ALL and TLX1 in T-ALL.…”

NKL Homeobox Gene VENTX Is Part of a Regulatory Network in Human Conventional Dendritic Cells

“…This code comprises eleven genes and enables differentiation of normal and aberrant expression of NKL homeobox genes in leukemia and lymphoma patient samples. Recently, the basic roles of NKL homeobox genes in regulation of normal and abnormal developmental hematopoietic processes have been reviewed [ 8 ]. For example, NKL homeobox gene NANOG is normally expressed only in early stages of hematopoiesis and aberrantly activated in acute myeloid leukemia (AML) patients [ 7 ].…”