Temporal dynamics of gene expression inform cellular and molecular perturbations associated with disease development and evolution. Given the complexity of high-dimensional temporal genomic data, an analytic framework guided by a robust theory is needed to interpret time-sequential changes and to predict system dynamics. Here we model temporal dynamics of the transcriptome of peripheral blood mononuclear cells in a two-dimensional state-space representing states of health and leukemia using time-sequential bulk RNA-seq data from a murine model of acute myeloid leukemia (AML). The statetransition model identified critical points that accurately predict AML development and identifies stepwise transcriptomic perturbations that drive leukemia progression. The geometry of the transcriptome state-space provided a biological interpretation of gene dynamics, aligned gene signals that are not synchronized in time across mice, and allowed quantification of gene and pathway contributions to leukemia development. Our statetransition model synthesizes information from multiple cell types in the peripheral blood and identifies critical points in the transition from health to leukemia to guide interpretation of changes in the transcriptome as a whole to predict disease progression. Significance: These findings apply the theory of state transitions to model the initiation and development of acute myeloid leukemia, identifying transcriptomic perturbations that accurately predict time to disease development. See related commentary by Kuijjer, p. 3072

Chronic lymphocytic leukemia (CLL) is a malignancy of mature lymphocytes that is manifest by the progressive accumulation of transformed cells, mostly due to their decreased apoptosis. CD84 belongs to the Signaling Lymphocyte Activating Molecule (SLAM) family of immunoreceptors and has an as yet unknown function in normal B cells and CLL lymphocytes. We show that CD84 is over-expressed in CLL cells. Activation of cell surface CD84 initiates a signaling cascade, which enhances cell survival. Both immunoneutralization or blockade of CD84 induce cell death in vitro and in vivo. Thus, overexpression of CD84 from an early stage may be critical for the survival of CLL. These findings suggest novel therapeutic strategies based on the blockade of a CD84 dependent survival pathway.

Chronic lymphocytic leukemia (CLL) is a malignant disease of small mature lymphocytes. Signals from the CLL microenvironment promote progression of the disease and induce drug resistance. This phenomenon is largely dependent on direct contact between the malignant B cells and stromal cells. CD84 belongs to the signaling lymphocyte activation molecule family of immunoreceptors, which self-associates, forming an orthogonal homophilic dimer. We therefore hypothesized that CD84 may bridge between CLL cells and their microenvironment, promoting cell survival. Our in vitro results show that CD84 expressed on CLL cells interact with CD84 expressed on cells in their microenvironment, inducing cell survival in both sides. Blocking CD84 in vitro and in vivo disrupt the interaction of CLL cells with their microenvironment, resulting in induced cell death. Thus, our findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway.

Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, is characterized by the progressive accumulation of small mature CD5+B lymphocytes in the peripheral blood, lymphoid organs, and bone marrow (BM). The main feature of the disease is decreased apoptosis, resulting in the pathologic accumulation of these malignant cells. Appropriate cellular responses to changes in oxygen tension during normal development or pathological processes, such as cardiovascular disease and cancer, are ultimately regulated by the transcription factor, hypoxia‐inducible factor (HIF). Unlike their normal counterparts, CLL cells express HIF‐1α even under normoxia. In addition, overexpression of HIF‐1α has been observed in leukemic cells in BM specimens from CLL patients. The HIF transcription factor has been implicated in controlling the expression of a wide variety of genes implicated in apoptosis, angiogenesis, invasion, and metastasis. This review describes pathways regulating CLL survival with a focus on HIF‐1α and its target genes, MIF and Midkine (MK), and the potential cross‐talk between these factors.

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