Myc Roles in Hematopoiesis and Leukemia

Abstract

Hematopoiesis is a process capable of generating millions of cells every second, as distributed in many cell types. The process is regulated by a number of transcription factors that regulate the differentiation along the distinct lineages and dictate the genetic program that defines each mature phenotype. Myc was first discovered as the oncogene of avian leukemogenic retroviruses; it was later found translocated in human lymphoma. From then on, evidence accumulated showing that c-Myc is one of the transcription factors playing a major role in hematopoiesis. The study of genetically modified mice with overexpression or deletion of Myc has shown that c-Myc is required for the correct balance between self-renewal and differentiation of hematopoietic stem cells (HSCs). Enforced Myc expression in mice leads to reduced HSC pools owing to loss of self-renewal activity at the expense of increased proliferation of progenitor cells and differentiation. c-Myc deficiency consistently results in the accumulation of HSCs. Other models with conditional Myc deletion have demonstrated that different lineages of hematopoietic cells differ in their requirement for c-Myc to regulate their proliferation and differentiation. When transgenic mice overexpress c-Myc or N-Myc in mature cells from the lymphoid or myeloid lineages, the result is lymphoma or leukemia. In agreement, enforced expression of c-Myc blocks the differentiation in several leukemia-derived cell lines capable of differentiating in culture. Not surprising, MYC deregulation is recurrently found in many types of human lymphoma and leukemia. Whereas MYC is deregulated by translocation in Burkitt lymphoma and, less frequently, other types of lymphoma, MYC is frequently overexpressed in acute lymphoblastic and myeloid leukemia, through mechanisms unrelated to chromosomal translocation, and is often associated with disease progression.

RNAi profiling of primary human AML cells identifies ROCK1 as a therapeutic target and nominates fasudil as an antileukemic drug

“…However, the destabilization of c-MYC, observed in ROCK inhibitor-treated prostate cancer cells, 39 might have played a role because this oncogene is frequently deregulated in AML. 41 Although the precise mode of action by which ROCK1 inhibition reduced leukemic burden in our in vitro and in vivo experiments was beyond the focus of our research, our results suggest that further exploration of ROCK1 inhibition as a potential antileukemic strategy is warranted. Even though our data in additional primary AML donors are limited in number, they are well in line with data generated by other groups in CML.…”

Far Upstream Element Binding Protein Plays a Crucial Role in Embryonic Development, Hematopoiesis, and Stabilizing Myc Expression Levels

“…Although beyond the scope of this article, investigation of conditional Fubp1 À/À cells would help to define better the role of FBP in hematopoiesis, with the use of a strategy similar to that used for delineating MYC function in hematopoiesis as reviewed. 52 A transcriptional map of human hematopoietic cells suggests that FBP is an important regulator of an expression module up-regulated in HSCs and primitive erythroid cells. 46 Therefore, conditional deletion of FBP in lymphoid progenitors (with the use of RAG1-Cre, Lck-Cre, or CD4-Cre) may be expected to be less deleterious than deletion of FBP in HSC (through a Vav-Cre) or erythroid progenitors (GATA1-Cre).…”

Triggering Fbw7-Mediated Proteasomal Degradation of c-Myc by Oridonin Induces Cell Growth Inhibition and Apoptosis

“…6B), suggesting that the deregulated c-Myc in leukemia and lymphoma cells was oncogenic rather that tumor-suppressive. Because of its oncogenic properties, c-Myc has been investigated and shown to be an effective target for cancer therapy (8,10,38). Because proteins are the executors of cell function, promoting the degradation of the c-Myc protein by oridonin may be more efficient than other strategies aimed at disrupting c-myc expression.…”