The development of cancer is intimately associated with genetic abnormalities that target proteins with intrinsically disordered regions (IDRs). In human haematological malignancies, recurrent chromosomal translocation of nucleoporin (NUP98 or NUP214) generates an aberrant chimera that invariably retains the nucleoporin IDR—tandemly dispersed repeats of phenylalanine and glycine residues1,2. However, how unstructured IDRs contribute to oncogenesis remains unclear. Here we show that IDRs contained within NUP98–HOXA9, a homeodomain-containing transcription factor chimera recurrently detected in leukaemias1,2, are essential for establishing liquid–liquid phase separation (LLPS) puncta of chimera and for inducing leukaemic transformation. Notably, LLPS of NUP98–HOXA9 not only promotes chromatin occupancy of chimera transcription factors, but also is required for the formation of a broad ‘super-enhancer’-like binding pattern typically seen at leukaemogenic genes, which potentiates transcriptional activation. An artificial HOX chimera, created by replacing the phenylalanine and glycine repeats of NUP98 with an unrelated LLPS-forming IDR of the FUS protein3,4, had similar enhancing effects on the genome-wide binding and target gene activation of the chimera. Deeply sequenced Hi-C revealed that phase-separated NUP98–HOXA9 induces CTCF-independent chromatin loops that are enriched at proto-oncogenes. Together, this report describes a proof-of-principle example in which cancer acquires mutation to establish oncogenic transcription factor condensates via phase separation, which simultaneously enhances their genomic targeting and induces organization of aberrant three-dimensional chromatin structure during tumourous transformation. As LLPS-competent molecules are frequently implicated in diseases1,2,4–7, this mechanism can potentially be generalized to many malignant and pathological settings. The NUP98–HOXA9 oncogenic fusion protein found in leukaemia undergoes phase separation in the nucleus, which helps to promote activation of leukaemic genes and to establish aberrant chromatin looping.

Phase separation drives aberrant chromatin looping and cancer development

Cytogenetic abnormalities are important aspects of patient diagnosis, risk assessment, and treatment in acute leukemia. Characteristic genetic abnormalities are recognized as important for disease classification and are a significant element of the 2008 World Health Organization (WHO) classification [1]. Some aberrations are involved in the initiation whereas others participate in the progression of different acute leukemias.

Cytogenetics of Acute Leukemia

Identification of the thyroid transcription factors (TTFs), NKX2-1, FOXE1, PAX8 and HHEX, has considerably advanced our understanding of thyroid development, congenital thyroid disorders and thyroid cancer. The TTFs are fundamental to proper formation of the thyroid gland and for maintaining the functional differentiated state of the adult thyroid; however, they are not individually required for precursor cell commitment to a thyroid fate. Although knowledge of the mechanisms involved in thyroid development has increased, the full complement of genes involved in thyroid gland specification and the signals that trigger expression of the genes that encode the TTFs remain unknown. The mechanisms involved in thyroid organogenesis and differentiation have provided clues to identifying the genes that are involved in human congenital thyroid disorders and thyroid cancer. Mutations in the genes that encode the TTFs, as well as polymorphisms and epigenetic modifications, have been associated with thyroid pathologies. Here, we summarize the roles of the TTFs in thyroid development and the mechanisms by which they regulate expression of the genes involved in thyroid differentiation. We also address the implications of mutations in TTFs in thyroid diseases and in diseases not related to the thyroid gland.

Thyroid transcription factors in development, differentiation and disease

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy that originates from leukemia-initiating cells (LICs). The identification of common mechanisms underlying LIC development will be important in establishing broadly effective therapeutics for AML. Constitutive NF-κB pathway activation has been reported in different types of AML; however, the mechanism of NF-κB activation and its importance in leukemia progression are poorly understood. Here, we analyzed myeloid leukemia mouse models to assess NF-κB activity in AML LICs. We found that LICs, but not normal hematopoietic stem cells or non-LIC fractions within leukemia cells, exhibited constitutive NF-κB activity. This activity was maintained through autocrine TNF-α secretion, which formed an NF-κB/TNF-α positive feedback loop. LICs had increased levels of active proteasome machinery, which promoted the degradation of IκBα and further supported NF-κB activity. Pharmacological inhibition of the proteasome complex markedly suppressed leukemia progression in vivo. Conversely, enhanced activation of NF-κB signaling expanded LIC frequency within leukemia cell populations. We also demonstrated a strong correlation between NF-κB activity and TNF-α secretion in human AML samples. Our findings indicate that NF-κB/TNF-α signaling in LICs contributes to leukemia progression and provide a widely applicable approach for targeting LICs.

/pdf/positive-feedback-between-nf-kb-and-tnf-a-promotes-leukemia-405tmjpxaz.pdf

Positive feedback between NF-κB and TNF-α promotes leukemia-initiating cell capacity

Nuclear pore proteins and cancer.

Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.

Retroviral expression of leukemogenic oncogenes in the murine hematopoietic system is essential but not sufficient to induce acute leukemia. Proviral integration-mediated elevated expression of the meningioma 1 (MN1) oncogene suggested MN1 acting as cooperating event in mixed-lineage leukemia 1 (MLL) and eleven nineteen leukemia (ENL)-induced murine leukemia. Indeed, co-expression of MN1 with MLL-ENL enhanced transformation in vivo, and resulted in a significantly reduced latency for induction of an aggressive acute leukemia when compared with MN1 or MLL-ENL alone. In addition, co-expression of MN1 increased the granulocyte macrophage progenitor cell population with leukemia-initiating properties as shown in secondary transplantation experiments. Gene expression profiling experiments identified putative downstream MN1 targets, of which FMS-like tyrosine kinase 3 (FLT3) and CD34 were upregulated in both MN1-overexpressing murine leukemias and in pediatric acute leukemias with high MN1 levels. Interestingly, small interfering RNA (siRNA)-mediated MN1 knockdown resulted in cell cycle arrest and impaired clonogenic growth of human leukemia cell lines with high MN1 levels. Our work shows for the first time that high MN1 levels are important for the growth of leukemic cells, and that increased MN1 expression can synergize with MLL-ENL and probably other transforming fusion genes in leukemia induction through a distinct gene expression program that is able to expand the leukemia-initiating cell population.

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia.

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Leukemogenic mechanisms and targets of a NUP98/HHEX fusion in acute myeloid leukemia.

Functional characterization of high levels of meningioma 1 as collaborating oncogene in acute leukemia.