scholarly journals EZH2 in Myeloid Malignancies

Cells ◽  
2020 ◽  
Vol 9 (7) ◽  
pp. 1639 ◽  
Author(s):  
Jenny Rinke ◽  
Andrew Chase ◽  
Nicholas C. P. Cross ◽  
Andreas Hochhaus ◽  
Thomas Ernst
Keyword(s):  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Loss Of Function ◽  
Disease Pathogenesis ◽  
Catalytic Core ◽  
Myeloid Malignancies ◽  
Treatment Free Remission

Our understanding of the significance of epigenetic dysregulation in the pathogenesis of myeloid malignancies has greatly advanced in the past decade. Enhancer of Zeste Homolog 2 (EZH2) is the catalytic core component of the Polycomb Repressive Complex 2 (PRC2), which is responsible for gene silencing through trimethylation of H3K27. EZH2 dysregulation is highly tumorigenic and has been observed in various cancers, with EZH2 acting as an oncogene or a tumor-suppressor depending on cellular context. While loss-of-function mutations of EZH2 frequently affect patients with myelodysplastic/myeloproliferative neoplasms, myelodysplastic syndrome and myelofibrosis, cases of chronic myeloid leukemia (CML) seem to be largely characterized by EZH2 overexpression. A variety of other factors frequently aberrant in myeloid leukemia can affect PRC2 function and disease pathogenesis, including Additional Sex Combs Like 1 (ASXL1) and splicing gene mutations. As the genetic background of myeloid malignancies is largely heterogeneous, it is not surprising that EZH2 mutations act in conjunction with other aberrations. Since EZH2 mutations are considered to be early events in disease pathogenesis, they are of therapeutic interest to researchers, though targeting of EZH2 loss-of-function does present unique challenges. Preliminary research indicates that combined tyrosine kinase inhibitor (TKI) and EZH2 inhibitor therapy may provide a strategy to eliminate the residual disease burden in CML to allow patients to remain in treatment-free remission.

scholarly journals Late molecular recurrences in patients with chronic myeloid leukemia experiencing treatment-free remission

2020 ◽  
Vol 4 (13) ◽  
pp. 3034-3040 ◽  
Author(s):  
Philippe Rousselot ◽  
Clémence Loiseau ◽  
Marc Delord ◽  
Jean Michel Cayuela ◽  
Marc Spentchian
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Molecular Response ◽  
Residual Rate ◽  
Treatment Free Remission

Abstract Treatment-free remission (TFR) is an opportunity for patients with chronic myeloid leukemia (CML). Reported cumulative incidence curves of molecular recurrence (MRec) arbor a 2-phase shape with mainly early events, but also some late events (late MRec [LMRec]). Having discontinued our first patient in 2004, we have access to a prolonged follow-up, enabling us to characterize these late events. Over 15 years, 128 patients from our institution were registered in the Stop Imatinib (STIM; A Study for Tyrosine Kinase Inhibitors Discontinuation [A-STIM]) trial. MRec was defined by the loss of major molecular response (BCR-ABL1IS >0.1%). At the first TFR attempt, patients had been taking a tyrosine kinase inhibitor for a median of 7.1 years and in BCR-ABL1IS ≤0.01% (MR4) for a median of 4 years. The median follow-up of patients in TFR was 6.5 years. The TFR rate was estimated to be 45.6% after 7 years. For 9/65 (14%) patients experiencing MRec, recurrence occurred after 2 years in TFR (median, 3.6 years). The residual rate of MRec after 2 years was estimated to be 18%. The probability of remaining in TFR was 65.4% for patients having experienced fluctuations of their minimal residual disease (MRD) (at least 2 consecutive measurements BCR-ABL1IS >0.0032% or loss of MR4), whereas it was 100% for those with stable MRD (P = .003). After 2 years in TFR, we observed an 18% residual rate of LMRec. These late events represent 14% of all MRec and occur in patients with fluctuating MRD measurements. A long-term molecular follow-up therefore remains mandatory for CML patients in TFR. The A-STIM study was registered at www.clinicaltrials.gov as #NCT02897245.

scholarly journals The importance of evaluating specific myeloid malignancies in epidemiological studies of environmental carcinogens

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
K. A. Mundt ◽  
L. D. Dell ◽  
P. Boffetta ◽  
E. M. Beckett ◽  
H. N. Lynch ◽  
...  
Keyword(s):  
Tobacco Smoking ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Epidemiological Studies ◽  
Sufficient Evidence ◽  
International Agency ◽  
Environmental Carcinogens ◽  
Epidemiological Evidence ◽  
Myeloid Malignancies ◽  
Chemical Agents

Abstract Introduction Although myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), myeloproliferative neoplasms (MPN) – including chronic myeloid leukemia (CML) – and myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are largely clinically distinct myeloid malignancies, epidemiological studies rarely examine them separately and often combine them with lymphoid malignancies, limiting possible etiological interpretations for specific myeloid malignancies. Methods We systematically evaluated the epidemiological literature on the four chemical agents (1,3-butadiene, formaldehyde, benzene, and tobacco smoking, excluding pharmaceutical, microbial and radioactive agents, and pesticides) classified by the International Agency for Research on Cancer as having sufficient epidemiological evidence to conclude that each causes “myeloid malignancies.” Literature searches of IARC Monographs and PubMed identified 85 studies that we critically assessed, and for appropriate subsets, summarized results using meta-analysis. Results Only two epidemiological studies on 1,3-butadiene were identified, but reported findings were inadequate to evaluate specific myeloid malignancies. Studies on formaldehyde reported results for AML and CML – and not for MDS or MPN – but reported no increased risks. For benzene, several specific myeloid malignancies were evaluated, with consistent associations reported with AML and MDS and mixed results for CML. Studies of tobacco smoking examined all major myeloid malignancies, demonstrating consistent relationships with AML, MDS and MPN, but not with CML. Conclusions Surprisingly few epidemiological studies present results for specific myeloid malignancies, and those identified were inconsistent across studies of the same exposure, as well as across chemical agents. This exercise illustrates that even for agents classified as having sufficient evidence of causing “myeloid malignancies,” the epidemiological evidence for specific myeloid malignancies is generally limited and inconsistent. Future epidemiological studies should report findings for the specific myeloid malignancies, as combining them post hoc – where appropriate – always remains possible, whereas disaggregation may not. Furthermore, combining results across possibly discrete diseases reduces the chances of identifying important malignancy-specific causal associations.

scholarly journals Lineage of measurable residual disease in patients with chronic myeloid leukemia in treatment-free remission

Leukemia ◽  
2019 ◽  
Vol 34 (4) ◽  
pp. 1052-1061 ◽  
Author(s):  
Ilaria S. Pagani ◽  
Phuong Dang ◽  
Verity A. Saunders ◽  
Randall Grose ◽  
Naranie Shanmuganathan ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Treatment Free Remission ◽  
Measurable Residual Disease

Decision-Making At The End Of Consolidation Of Acute Myeloid Leukemia: Negative Effect Of Minimal Residual Disease Detectable With Multiparametric Flowcytometry Combined With Gene Mutations Of FLT3 On Early Relapse

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3921-3921
Author(s):  
Yuichiro Ono ◽  
June Takeda ◽  
Hayato Maruoka ◽  
Yasuhiro Kazuma ◽  
Nobuhiro Hiramoto ◽  
...  
Keyword(s):  
Decision Making ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Gene Mutations ◽  
Decision Making Process ◽  
Consolidation Therapy ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Minimal Residual ◽  
Acute Myeloid

Abstract Background About 70-80% of adult patients (pts) with acute myeloid leukemia (AML) achieve complete remission (CR); however, around a half of them experience a relapse. For the purpose of creating accurate decision-making process of post-consolidation strategy, stratification system using karyotype and recurrent gene mutations have been widely utilized. As is confirmed in childhood acute lymphocytic leukemia, however, the information of minimal residual disease (MRD) status would substantially improve the reliance of decision-making process of adult AML pts. Unfortunately, approximately a half of AML patients lack molecular targets suitable for MRD monitoring. The aims of this study are to evaluate the applicability of MRD detection using multiparametric flow cytometry (MPFC) and to estimate the impact of MRD measured with MPFC at the end of consolidation therapy in improving decision-making process. Patients and Methods We retrospectively studied 81 consecutive pts with newly diagnosed AML who received induction therapies and achieved CR in our institute between January 2007 and March 2013. Pts with acute promyelocytic leukemia were excluded. We routinely analyzed the bone marrow specimens with MPFC for the detection of leukemia-associated immunophenotypes (LAIPs) at diagnosis. Since April 2010, RT-PCR assay examined FLT3-ITD mutation in the same specimens. In pts who had traceable LAIPs, the relationships of the levels of MRD at the end of consolidation therapy with relapse free survival were analyzed. Positive MRD was defined as the detection of 0.2% and more LAIPs-positive cells with MPFC. We compared two patient groups: those with MRD at the end of consolidation (MRDp group) and those without (MRDn group). Relapse-free survival (RFS) was analyzed using the Kaplan-Meier method and the log-rank test was used for comparison between each group. A multivariate Cox regression analysis for RFS was fit to assess the effect of the followings: age at diagnosis (≥ vs. < 65 years old), the number of induction regimens required for achieving CR (≥ vs. < 2 times), cytogenetic risk groups of SWOG (unfavorable vs. favorable/intermediate). Results In 57 / 81 pts, MPFC could detect LAIPs in the bone marrow specimens at diagnosis (70.4% of all subjects; 15-82 years-old; follow-up time [median] 98-2211[517] days). FLT-ITD mutations were found in 13 pts, but not in 39 pts (the remaining 5 pts were not examined). The rate of detection of LAIPs with 6-color MPFC was significantly superior to 3-color MPFC (82.1% vs. 61.0%, p<0.05). Induction chemotherapies the pts received were anthracyclin-containing regimens, such as idarubicin and cytarabin (3+7), in 52 pts (91.2%), low-dose cytarabin-based regimen in 4 pts (7.0%) and azacitidine in 1 pt. (1.8%). The MRDp and the MRDn groups were comprised of 20 and 37 pts (35.1% and 64.9%) , respectively. One-year RFS of the MRDp group was significantly inferior to the MRDn group (28.3% vs. 75.2%; log-rank p<0.0005). In the multivariable analysis using the model above, MRD positivity at the end of consolidation remains a significant predictor (HR, 2.93, 95% CI 1.16-7.45, p<0.05). In addition, the 1-year RFS in the MRDp group with FLT-ITD was significantly shorter than that in the MRDp group without FLT3-ITD (0% vs. 47.6% with positive and negative FLT3-ITD, log-rank p<0.05). In the MRDn group, however, the negative impact of FLT3-ITD was not documented (85.7% vs. 69.3% with positive and negative FLT3-ITD, log-rank p=0.954). Conclusion Our retrospective study confirmed that LAIPs as MRD targets were applicable to the majority of pts with AML; MRD positivity measured with LAIPs was a promising predictor for early relapses at the end of consolidation, as was previously reported. When combined with FLT-ITD status, it might become a more sensitive prognostic factor. Disclosures: Takahashi: celgene: Research Funding.

scholarly journals Impact of gene mutations on treatment response and prognosis of acute myeloid leukemia secondary to myeloproliferative neoplasms

2017 ◽  
Vol 93 (3) ◽  
pp. 330-338 ◽  
Author(s):  
Geoffroy Venton ◽  
Frédéric Courtier ◽  
Aude Charbonnier ◽  
Evelyne D'incan ◽  
Colombe Saillard ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Treatment Response ◽  
Myeloid Leukemia ◽  
Myeloproliferative Neoplasms ◽  
Gene Mutations ◽  
Acute Myeloid

scholarly journals Impact of NCCN Risk Stratification and Minimal Residual Disease on Allogeneic Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2296-2296
Author(s):  
Yue Lu ◽  
Tong Wu ◽  
Yan-Li Zhao ◽  
Xing-Yu Cao ◽  
De-Yan Liu ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Conditioning Regimen ◽  
Gene Mutations ◽  
Disease Status ◽  
Hematopoietic Stem ◽  
Secondary Aml ◽  
Donor Type ◽  
Minimal Residual

Abstract Introduction: Cytogenetic abnormality is considered to be an independent prognostic factor in newly diagnosed acute myeloid leukemia (AML). However, recent studies have demonstrated that acquired gene mutations also play an important role in the pathogenesis and prognosis of AML. It has been well known that minimal residual disease (MRD) pre-conditioning has remarkable impact on disease-free survival (DFS) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in acute lymphoblastic leukemia, but the effect of MRD pre-transplant on allo-HSCT in AML is still unclear. Objective: In present study, the effect of NCCN risk stratification which has integrated gene mutations into cytogenetics as well as MRD pre-transplant on DFS after allo-HSCT in AML was studied in order to learn whether risk-directed conditioning and prevention of relapse are needed. Methods: Between April 2012 and March 2015, consecutive 258 patients with AML in complete remission (CR) (186 cases in CR1 and 72 cases in CR2) who underwent allo-HSCT in our hospital were analyzed retrospectively. The median age was 25 (1.8-64) years. Male (M) to female (F) was 147:111. The median disease course was 6 (1-51) months. According to 2015-NCCN risk stratification, 63 (24.4%) cases were in low risk, 112 (43.4%) cases in intermediated risk, and 83 (32.2%) cases in high risk. MRD in bone marrow pre-conditioning was detected by eight-color flow cytometry. Results: With the median follow up 18 (5-41) months, overall 2-year DFS was78.0%. No significant difference in DFS was found among low-risk (78.6%), intermediated-risk (76.0%) and high-risk (80.3%) patients (P=0.886). 205 (79.5%) cases were MRD- and 53 (20.5%) cases were MRD+ before conditioning. DFS after transplant in MRD+ patients was significant lower than that in MRD- patients(65.0% vs. 81.4%, P=0.003). Univariate analysis showed that DFS was not associated with patient age (≤14years vs.>14years, P=0.292), disease course before HSCT (≤6 months vs.>6months, P=0.532), WBC counts at diagnosis (≤50×109/L vs.>50×109/L, P=0.120), CBC recovery pre-HSCT (yes vs. no, P=0.664), disease status (CR1 vs. CR2, P=0.201), extramedullary leukemia before transplant (yes vs. no, P=0.532), conditioning regimen (BUCy/Flu-based vs. TBICy/Flu-based, P=0.753), donor type (identical sibling vs. unrelated vs. haploidentical, P=0.743), donor-recipient gender (M-M vs. M-F vs. F-M vs. F-F, P=0.245), donor-recipient blood type (compatibility vs. major incompatibility vs. minor incompatibility vs. major and minor incompatibility, P=0.402), mononuclear cells infused (≤8×108/kg vs.>8×108/kg, P=0.583), CD34+ cells infused (≤4×106/kg vs.>4×106/kg, P=0.946), and CD3+ cells infused (≤1.6×108/kg vs.>1.6×108/kg, P=0.143). DFS was significant lower in the patients with secondary AML (79.4% in primary AML vs. 53.5% in secondary AML, P=0.006) and MRD+ cases before transplant (81.4% in MRD- vs. 65.0% in MRD+, P=0.003). Accumulative non-relapse mortality (NRM) was significant higher in secondary AML (11.7% in primary AML vs. 33.3% in secondary AML, P=0.004) and MRD+ patients (10.5% in MRD- vs. 21.9% in MRD+, P=0.010). Accumulative relapse rate was significant higher in CR2 cases (8.0% in CR1 vs. 17.5% in CR2, P=0.046). Multivariate analysis showed that MRD pre-HSCT was the only impact factor on DFS and NRM with higher DFS (P=0.020) and lower NRM (P=0.045) in MRD- cases. Conclusions: Allo-HSCT has attenuated the influence of cytogenetics and gene mutations on DFS in AML. Secondary AML has lower DFS and higher NRM. Although disease status (CR1 vs. CR2) has no significant influence on DFS, relapse rate in CR2 is higher than that in CR1. MRD pre-conditioning was a key impact factor on DFS after allo-HSCT in AML but not conditioning regimen and donor type. Disclosures No relevant conflicts of interest to declare.

scholarly journals Therapeutic inhibition of FcγRIIb signaling targets leukemic stem cells in chronic myeloid leukemia

Leukemia ◽  
2020 ◽  
Vol 34 (10) ◽  
pp. 2635-2647
Author(s):  
Oliver Parting ◽  
Samantha Langer ◽  
Maja Kim Kuepper ◽  
Caroline Wessling ◽  
Shaoguang Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Chronic Myeloid Leukemia ◽  
Therapeutic Approach ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Leukemic Stem Cells ◽  
Downstream Signaling ◽  
Targeted Inhibition ◽  
Treatment Free Remission

Abstract Despite the successes achieved with molecular targeted inhibition of the oncogenic driver Bcr-Abl in chronic myeloid leukemia (CML), the majority of patients still require lifelong tyrosine kinase inhibitor (TKI) therapy. This is primarily caused by resisting leukemic stem cells (LSCs), which prevent achievement of treatment-free remission in all patients. Here we describe the ITIM (immunoreceptor tyrosine-based inhibition motif)-containing Fc gamma receptor IIb (FcγRIIb, CD32b) for being critical in LSC resistance and show that targeting FcγRIIb downstream signaling, by using a Food and Drug Administration-approved BTK inhibitor, provides a successful therapeutic approach. First, we identified FcγRIIb upregulation in primary CML stem cells. FcγRIIb depletion caused reduced serial re-plaiting efficiency and cell proliferation in malignant cells. FcγRIIb targeting in both a transgenic and retroviral CML mouse model provided in vivo evidence for successful LSC reduction. Subsequently, we identified BTK as a main downstream mediator and targeting the Bcr-Abl-FcγRIIb-BTK axis in primary CML CD34+ cells using ibrutinib, in combination with standard TKI therapy, significantly increased apoptosis in quiescent CML stem cells thereby contributing to the eradication of LSCs.. As a potential curative therapeutic approach, we therefore suggest combining Bcr-Abl TKI therapy along with BTK inhibition.

scholarly journals Cooperative Epigenetic Regulation By ASXL1 and NF1 Loss on Leukemogenesis

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 652-652
Author(s):  
Peng Zhang ◽  
Fuhong He ◽  
Jie Bai ◽  
Shi Chen ◽  
Stephen D. Nimer ◽  
...  
Keyword(s):  
Disease Progression ◽  
Signaling Pathway ◽  
Mouse Models ◽  
Myeloid Leukemia ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Gene Mutations ◽  
Rna Seq ◽  
Ras Pathway ◽  
Myeloid Malignancies

Abstract Introduction: Additional sex combs-like 1 (ASXL1) is frequently mutated in a wide range of myeloid malignancies, including myelodysplastic syndrome (MDS), myeloproliferative neoplasm, chronic myelomonocytic leukemia, and acute myeloid leukemia (AML). Notably, ASXL1 mutations are generally associated with the poor clinical outcomes. We and others have established Asxl1 mouse models and demonstrated that loss of Asxl1 leads to MDS-like disease, which can transform to myeloid leukemia in aged mice. These studies suggest that additional mutations may cooperate with Asxl1 loss to induce the leukemia transformation. However, the molecular mechanisms underlying the leukemogenesis associated with ASXL1 and cooperating mutations remain to be elucidated. Methods: To identify cooperating events with ASXL1 mutations in myeloid malignancies, we recruited a cohort of 138 ASXL1 mutated patients and performed targeted exome sequencing. We then characterized the hematopoietic features using mouse models. A serial hematopoietic phenotypic analyses were used, including peripheral blood counts, flow cytometry, colony assay, morphology and transplantation assays. To decipher the molecular mechanisms by which loss of Asxl1 and Nf1 cooperate in promoting myeloid leukemia transformation, we performed RNA-seq and ChIP-seq to identify the differentially expressed genes and their associated histone modifications in four genotypes of mice, WT, Asxl1+/-, Nf1+/-, and Asxl1+/-;Nf1+/- mice. Finally, the leukemic mice were treated with pharmacologic inhibitors targeting both MAPK pathway and BET bromodomain in vivo as a proof-of-concept approach. Results: We analyzed the gene mutation profiles of 138 ASXL1 mutated patients based on targeted sequencing and found that 35 of these patients have gene mutations involving in RAS/MAPK signaling pathway, including NF1, NRAS, KRAS, PTPN11 or CBL. The incidence of AML was significantly higher in patients with RAS pathway mutations (48.6%) than in the cases without RAS pathway mutations (29.1%, p = 0.036, chi-square test). These data suggest that concomitant mutations of ASXL1 and RAS pathway genes associate with poor prognosis in myeloid malignancies. To validate the functional significance of cooperative mutations of ASXL1 and NF1, a negative regulator of the RAS signaling pathway, in the disease progression of myeloid leukemia, we generated Asxl1+/-;Nf1+/- and Mx1Cre;Asxl1fl/fl;Nf1fl/fl (Asxl1Δ/Δ;Nf1Δ/Δ) mice and performed hematopoietic phenotypic analyses. Asxl1 loss cooperates with haploinsufficiency of Nf1 to accelerate the development of myeloid leukemia in mice. Asxl1Δ/Δ;Nf1Δ/Δ mice displayed a rapid, progressive leukocytosis with severe anemia and thrombocytopenia 3-6 months after pIpC injection, indicative of aggressive myeloid leukemia with a 100% penetrance. Loss of Asxl1 and Nf1 in hematopoietic stem and progenitor cells lead to transcriptional activation of multiple pathways critical for leukemogenesis, such as MYC, NRAS, and BRD4. Convergent analysis of RNA-seq and ChIP-seq data reveal that the hyperactive MYC and BRD4 transcription program is correlated with elevated H3K4 tri-methylation at the promoter regions of genes involving these pathways. Importantly, pharmacological inhibition of both MAPK pathway and BET bromodomain prevents leukemia initiation and inhibits disease progression in Asxl1Δ/Δ;Nf1Δ/Δ mice, and significantly prolonged the survival of leukemic Asxl1+/-;Nf1+/- mice. Conclusion: This study sheds lights on the understanding of the cooperative effect between epigenetic alterations and signaling pathways in accelerating the progression of myeloid malignancies and provides a rationale therapeutic strategy for the treatment of myeloid malignancies with ASXL1 and RAS pathway gene mutations. Disclosures No relevant conflicts of interest to declare.

CD44 loss of function sensitizes AML cells to the BCL-2 inhibitor venetoclax by decreasing CXCL12-driven survival cues

Blood ◽  
2021 ◽  
Author(s):  
Xiaobing Yu ◽  
Leonel Munoz-Sagredo ◽  
Karolin Streule ◽  
Patricia Muschong ◽  
Elisabeth Bayer ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Residual Disease ◽  
Embryonic Stem ◽  
Xenograft Model ◽  
Standard Of Care ◽  
Loss Of Function ◽  
Current Standard ◽  
Induced Apoptosis ◽  
Biomolecular Fluorescence Complementation

Acute myeloid leukemia (AML) has a poor prognosis under the current standard of care. In recent years, venetoclax, a BCL-2 inhibitor, was approved to treat patients, ineligible for intensive induction chemotherapy. Complete remission rates with venetoclax-based therapies are, however, hampered by minimal residual disease (MRD) in a proportion of patients, leading to relapse. MRD is due to leukemic stem cells retained in bone marrow protective environments; activation of the CXCL12/CXCR4 pathway was shown to be relevant to this process. An important role is also played by cell adhesion molecules such as CD44, which has been shown to be crucial for AML development. Here we show that CD44 is involved in CXCL12 promotion of resistance to venetoclax-induced apoptosis in human AML cell lines and AML patient samples which could be abrogated by CD44 knockdown, knockout or blocking with an anti-CD44 antibody. Split-Venus biomolecular fluorescence complementation showed that CD44 and CXCR4 physically associate at the cell membrane upon CXCL12 induction. In the venetoclax-resistant OCI-AML3 cell line, CXCL12 promoted an increase in the proportion of cells expressing high levels of embryonic-stem-cell core transcription factors (ESC-TFs: Sox2, Oct4, Nanog), abrogated by CD44 knockdown. This ESC-TF-expressing subpopulation which could be selected by venetoclax treatment, exhibited a basally-enhanced resistance to apoptosis, and expressed higher levels of CD44. Finally, we developed a novel AML xenograft model in zebrafish, showing that CD44 knockout sensitizes OCI-AML3 cells to venetoclax treatment in vivo. Our study shows that CD44 is a potential molecular target to sensitize AML cells to venetoclax-based therapies.

Sign in / Sign up

Export Citation Format

Share Document