The Pluripotency Regulator PRDM14 Requires Hematopoietic Regulator CBFA2T3 to Initiate Leukemia in Mice

Abstract

PR domain-containing 14 (Prdm14) is a pluripotency regulator central to embryonic stem cell identity and primordial germ cell specification. Genomic regions containing PRDM14 are often amplified leading to misexpression in human cancer. Prdm14 expression in mouse hematopoietic stem cells (HSC) leads to progenitor cell expansion prior to the development of T-cell acute lymphoblastic leukemia (T-ALL), consistent with PRDM14's role in cancer initiation. Here, we demonstrate mechanistic insight into PRDM14-driven leukemias in vivo. Mass spectrometry revealed novel PRDM14-protein interactions including histone H1, RNA-binding proteins, and the master hematopoietic regulator CBFA2T3. In mouse leukemic cells, CBFA2T3 and PRDM14 associate independently of the related ETO family member CBFA2T2, PRDM14's primary protein partner in pluripotent cells. CBFA2T3 plays crucial roles in HSC self-renewal and lineage commitment, and participates in oncogenic translocations in acute myeloid leukemia. These results suggest a model whereby PRDM14 recruits CBFA2T3 to DNA, leading to gene misregulation causing progenitor cell expansion and lineage perturbations preceding TALL development. Strikingly, Prdm14induced TALL does not occur in mice deficient for Cbfa2t3, demonstrating that Cbfa2t3 is required for leukemogenesis. Moreover, TALL develops in Cbfa2t3 heterozygotes with a significantly longer latency, suggesting that PRDM14-associated TALL is sensitive to Cbfa2t3 levels. Our study highlights how an oncogenic protein uses a native protein in progenitor cells to initiate leukemia, providing insight into PRDM14-driven oncogenesis in other cell types. Implications: The pluripotency regulator PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells, demonstrating an oncogenic role for CBFA2T3 and providing an avenue for targeting cancerinitiating cells.

Multifaceted Role of PRDM Proteins in Human Cancer

“…More recently, in a derived inducible FLAG-PRDM14 mouse model, PRDM14-induced T-cell ALL was driven by activated Notch1 through a RAG-mediated deletion-based mechanism ( Figures 3E and 5) [194]. Furthermore, novel findings demonstrated that PRDM14 requires the master hematopoietic regulator CBFA2T3 to initiate leukemia in progenitor cells [195].…”

Reduction of RUNX1 transcription factor activity by a CBFA2T3-mimicking peptide: application to B cell precursor acute lymphoblastic leukemia

“…In myeloid differentiation, CBFA2T3 interacts with PU1 to repress stem cell genes [ 22 ]. CBFA2T3 can also partner with PRDM14 on DNA and participates in T-ALL development [ 39 ]. Finally, in B-cell lineage, and in Diffuse Large B-cell Lymphoma in particular, CBFA2T3 is reported to be part of the LMO2 complex regulating kinetochore function, chromosome assembly, and mitosis [ 40 ].…”

“…Globally, mouse models of RUNX1 overexpression do not lead directly to cancer by itself but increases cancer predisposition [ 47 , 48 ]. CBFA2T3 is required to initiate Prdm14 -induced T-acute lymphoblastic leukemia, demonstrating its oncogenic role [ 39 ]. Even though we demonstrated here an interaction between CBFA2T3 and ETV6-RUNX1 proteins, we did not obtain any evidence that CBFA2T3 could act directly onto ETV6-RUNX1 function.…”

Off to a Bad Start: Cancer Initiation by Pluripotency Regulator PRDM14

“…Despite evidence that protein-binding partners are critical for PRDM14's function, PRDM14's functional partners in a cancer model have only recently been described [40]. Interestingly, PRDM14's primary interacting partner in the T-ALL mouse model is CBFA2T3, a related family member to PRDM14's partner in PGCs, CBFA2T2.…”

“…It is possible that the ETO fusion proteins elevate expression levels of a pluripotency factor such as PRDM14, triggering genome instability; alternatively, it is possible that PRDM14-driven tumours have genome instability due to mis-appropriation of the ETO/CBFA2T family members. It is difficult to separate the CBFA2T3 and PRDM14 functions in mouse leukemias, since mice lacking CBFA2T3 do not have expanded hematopoietic progenitor cells and do not develop leukemia when PRDM14 is mis-expressed [40]. Certainly, the association of CSCs with genetic events that take place in progenitor cells rather than more differentiated cells may be explained by the hijacking of resident proteins.…”