Subclones of bone marrow CD34⁺ cells in acute myeloid leukemia at diagnosis confer responses of patients to induction chemotherapy

Abstract

Background: Acute myeloid leukemia (AML) is a hematopoietic malignancy with a prognosis that varies with genetic heterogeneity of hematopoietic stem/progenitor cells (HSPCs). Induction chemotherapy with cytarabine and anthracycline has been the standard care for newly diagnosed AML, but about 30% of patients have no response to this regimen. The resistance mechanisms require deeper understanding.Methods: In our study, using single-cell RNA sequencing, we analyzed the heterogeneity of bone marrow CD34 + cells from newly diagnosed patients with AML who were then divided into sensitive and resistant groups according to their responses to induction chemotherapy with cytarabine and anthracycline. We verified our findings by TCGA database, GEO datasets, and multiparameter flow cytometry. Results:We established a landscape for AML CD34 + cells and identified HSPC types based on the lineage signature genes. Interestingly, we found a cell population with CRIP1 high LGALS1 high S100As high showing features of granulocyte-monocyte progenitors was associated with poor prognosis of AML. And two cell populations marked by CD34 + CD52 + or CD34 + CD74 + DAP12 + were related to good response to induction therapy, showing characteristics of hematopoietic stem cells. Conclusion:Our study indicates the subclones of CD34 + cells confers for outcomes of AML and provides biomarkers to predict the response of patients with AML to induction chemotherapy.

Subclones with variants of uncertain clinical significance might contribute to ineffective hemopoiesis and leukemia predisposition

“…When considered only known pathogenic mutations, NPM1 , SRSF2 , ASXL1 , DNMT3A , IDH1 , NRAS , RUNX1 , BRAF , FLT3 , TET2 , and EZH2 in AML and MDS were commonly mutated, with SF3B1 and TP53 only in MDS. Our findings confirmed that a small number of genes is frequently mutated in AML and MDS, proving their driver role in leukemogenesis 35 . However, differently from previous studies, we proposed both known pathogenic variants and VUS as a marker of clonal hemopoiesis, that can be also found in subjects with CCUS and that might have clinical significance in a setting of complex and heterogeneous clonal hemopoiesis.…”

“…Our findings confirmed that a small number of genes is frequently mutated in AML and MDS, proving their driver role in leukemogenesis. 35 NRAS, ASXL1, RUNX1, and SETBP1 gene mutations are mutated only in less than 10% of MDS cases, even though are independent risk factors for inferior survival and the increased risk to AML transformation. 32,36 SETBP1, a 170-kDa nuclear protein that binds to SET protein, to AT-rich DNA regions-"AAAATAA/T" sequences, to promoter regions of genes involved in hemopoiesis, such as HOXA9, HOXA10, and RUNX1, 31,[37][38][39][40] to members of the KMT2A (lysine methyltransferase)-COMPASS (COMplex of Proteins ASsociated with SET1) family ultimately leading to methylation regulation of promoter regions of the HOX genes, 37 or to modified histones.…”

Big data and single‐cell sequencing in acute myeloid leukemia research

“…By comparing sensitive AML patients with those who are resistant, they found that cell populations with CRIP1 high LGALS1 high S100As high exhibiting the features of granulocyte–monocyte progenitors were associated with adverse prognosis of AML. Moreover, two cell populations marked by CD34 + CD52 + or CD34 + CD74 + DAP12 + were associated with good response to induction therapy 151 …”

“…Moreover, two cell populations marked by CD34 + CD52 + or CD34 + CD74 + DAP12 + were associated with good response to induction therapy. 151 Some studies provided an opportunity for prognosis prediction in patients with AML. Lu et al 152 identified various immune subtypes present in AML and built a model with nine prognostic biomarkers to predict the prognosis of patients with diverse immune cell infiltration clusters.…”

“…Using scRNA‐seq, Zhang et al 150 found that abnormally expressed B7 family molecules affected the prognosis of AML patients, which means they may serve as promising prognostic biomarkers and candidate therapeutic targets. With scRNA‐seq, Jia et al 151 established a landscape for AML CD34 + cells and identified HSPC types based on the lineage signature genes. By comparing sensitive AML patients with those who are resistant, they found that cell populations with CRIP1 high LGALS1 high S100As high exhibiting the features of granulocyte–monocyte progenitors were associated with adverse prognosis of AML.…”