Helicase-like transcription factor is a RUNX1 target whose downregulation promotes genomic instability and correlates with complex cytogenetic features in acute myeloid leukemia

Abstract

H elicase-like transcription factor is a SWI/SNF chromatin remodeling factor involved in various biological processes. However, little is known about its role in hematopoiesis. In this study, we measured helicase-like transcription factor mRNA expression in the bone marrow of 204 adult patients with de novo acute myeloid leukemia. Patients were dichotomized into low and high expression groups at the median level for clinicopathological correlations. Helicaselike transcription factor levels were dramatically reduced in the low expression patient group compared to those in the normal controls (n=40) (P<0.0001). Low helicase-like transcription factor expression correlated positively with French-American-British M4/M5 subtypes (P<0.0001) and complex cytogenetic abnormalities (P=0.02 for ≥3 abnormalities; P=0.004 for ≥5 abnormalities) but negatively with CEBPA double mutations (P=0.012). Also, low expression correlated with poorer overall (P=0.005) and event-free (P=0.006) survival in the intermediate-risk cytogenetic subgroup. Consistent with the more aggressive disease associated with low expression, helicase-like transcription factor knockdown in leukemic cells promoted proliferation and chromosomal instability that was accompanied by downregulation of mitotic regulators and impaired DNA damage response. The significance of helicase-like transcription factor in genome maintenance was further indicated by its markedly elevated expression in normal human CD34 + hematopoietic stem cells. We further demonstrated that helicase-like transcription factor was a RUNX1 target and transcriptionally repressed by RUNX1-ETO and site-specific DNA methylation through a duplicated RUNX1 binding site in its promoter. Taken together, our findings provide new mechanistic insights on genomic instability linked to helicase-like transcription factor deregulation, and strongly suggest a tumor suppressor function of the SWI/SNF protein in acute myeloid leukemia.

RUNX1 mutations promote leukemogenesis of myeloid malignancies in ASXL1-mutated leukemia

“…On the other hand, we could not detect ASXL1 or RUNX1 mutations in CML patients at initial diagnosis of chronic phase; however, acquisition of RUNX1 and/or ASXL1 mutations occurred in 25.5% (13/51) of patients during AML transformation. Moreover, 3 of the 6 CML-myeloid BC patients carrying ASXL1 mutations had co-existence of RUNX1 and ASXL1 mutations [18]. To further investigate the role of RUNX1 mutations to the myeloid transformation in ASXL1-mutated leukemia, we performed in vitro and in vivo expressing either ASXL1 or RUNX1 single mutant or combination of ASXL1 with RUNX1 mutant.…”

“…We also observed that RUNX1 and ASXL1 mutations frequently coexisted in CMML [17]. In addition, we found that the clonal evolution of RUNX1 and/or ASXL1 mutations occurred most frequently in CML with myeloid BC [18]. We had previously shown that the biological activities of RUNX1 mutants predicted sAML transformation from CMML and MDS [19].…”

HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro

“…Mechanistic studies have revealed that HLTF suppresses the motility of CRC cells via the TGF-β signaling pathway. In 2016, Cheng et al demonstrated that HLTF expression was reduced in adult acute myeloid leukemia patients with more aggressive disease phenotypes (34). In this study, the results of immunohistochemistry revealed that HLTF expression was negatively associated with the differentiation status, tumor invasive depth, lymph metastasis and distant metastasis in CRC.…”

Dictys: dynamic gene regulatory network dissects developmental continuum with single-cell multi-omics

“…2g). HLTF, a known SWI/SNF chromatin remodeler in pro-erythroid cells implicated in genomic instability in acute myeloid leukemia 50,54 , also had elevated regulatory activity in Erythroid cells (Fig. 2de) with prominent inferred targets such as BCL11A and UBAC1 35,55 (Fig.…”

“…Although both differential analyses of Erythroid versus Progenitor cells recovered many established TFs (e.g. GATA1, GFIB, FOXO4 for Erythroid cells and HLF, KLF4 for Progenitors [31][32][33][34][35]46 ), several TFs with Erythroidspecific functions exhibited much stronger logFCs in differential regulation, such as TFCP2 and RREB1 (hemoglobin regulators 47,48 ), HLTF, ZKSCAN3, NFE2L2, etc [49][50][51] (Fig. 2d, Supplementary Table 1).…”