Early loss of Crebbp confers malignant stem cell properties on lymphoid progenitors

Abstract

Loss-of-function mutations of cyclic-AMP response element binding protein, binding protein (CREBBP) are prevalent in lymphoid malignancies. However, the tumour suppressor functions of CREBBP remain unclear. We demonstrate that loss of Crebbp in murine haematopoietic stem and progenitor cells (HSPC) leads to increased development of B-cell lymphomas. This is preceded by accumulation of hyperproliferative lymphoid progenitors with a defective DNA damage response (DDR) due to a failure to acetylate p53. We identify a pre-malignant lymphoma stem cell population with decreased H3K27ac, which undergoes transcriptional and genetic evolution due to the altered DDR, resulting in lymphomagenesis. Importantly, when Crebbp is lost later in lymphopoiesis, cellular abnormalities are lost and tumour generation attenuated. We also document that CREBBP mutations may occur in HSPC from patients with CREBBP-mutated lymphoma. These data suggest that earlier loss of Crebbp is advantageous for lymphoid-transformation and inform the cellular origins and subsequent evolution of lymphoid malignancies.

TET2 Deficiency Causes Germinal Center Hyperplasia, Impairs Plasma Cell Differentiation, and Promotes B-cell Lymphomagenesis

“…CREBBP mutations are generally described as early lesions in DLBCL and induce a similar phenotype as Tet2 deficiency with defective PC formation (12,55). Along these lines it is notable that TET2 somatic mutations have been demonstrated to be present in the HSCs of TET2 mutant DLBCL patients and are present at high variant allele frequencies in DLBCL.…”

Precision medicine and lymphoma

“…Given the frequency and recognition of CREBBP mutations as one of the earliest events in GC lymphomas [8][9][10][11][58][59][60], and their widespread role in promoting GClymphoma development [4,[58][59][60][61][62], the successful targeting of these lesions would offer an exciting new therapy with the potential to eradicate disease-propagating cells. Indeed, phylogenetic analysis has revealed that overt FL, and subsequent relapses of the disease, are likely to develop from long-lived pre-malignant cells known as common progenitor cells (CPCs), which are believed to be t(14;18)-positive and typically contain mutations within the histone regulatory genes CREBBP and KMT2D [1,[3][4][5][63][64][65][66].…”

Downregulating CREBBP inhibits proliferation and cell cycle progression and induces daunorubicin resistance in leukemia cells

“…Genome-wide profiling studies, including DNA microarray and next generation sequencing have identified several genetic alterations associated with childhood ALL ( 1 – 3 ) CREB-binding protein (CREBBP) gene translocations have been observed in de novo ALL, and its mutations are enriched in relapsed pediatric patients with ALL and newly diagnosed patients with high hyperdiploid karyotype, with the potential of recurrence ( 4 – 6 ). It has been revealed that early loss of CREBBP confers murine malignant stem cell properties on lymphoid progenitors ( 7 ). Furthermore, a previous study reported that low CREBBP mRNA expression was associated with a high level of minimal residual disease (MRD) at the end of induction therapy and adverse long-term outcomes in pediatric patients with ALL, and suggested that the negative effect of CREBBP on prognosis may be improved with intensive chemotherapy ( 8 ).…”