Impact of anemia on the outcomes of chronic phase chronic myeloid leukemia in TKI era

Liu, Zhenyou; Shi, Yuye; Zhang, Yan; He, Zhengmei; Ding, Banghe; Tao, Shandong; Li, Yunjie; Yu, Liang

doi:10.1080/16078454.2020.1765563

Cited by 13 publications

(7 citation statements)

References 9 publications

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“…Although the HB value was not included in the four scoring systems, CML-CP patients with moderate anemia showed more aggressive characteristics, such as higher WBC counts and a higher percent of myeloblasts and BAS, than nonmoderate anemia patients [ 26 ]. This could be partly explained by the high levels of hematopoietic stem cells, which alter the components in the bone marrow microenvironment and elicit defective hematopoiesis in CML patients [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

Chen²,

Xu³

et al. 2022

Cancers

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A proportion of patients with somatic variants show resistance or intolerance to TKI therapy, indicating additional mutations other than BCR∷ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients at diagnosis to explore the mutation spectrum other than BCR∷ABL1 affecting the achievement of molecular responses. The most frequently mutated gene was ASXL1 (40.9%). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months. The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR4.0 at 36 months (p = 0.023). The achievement of MR4.5 at 12 months was adversely impacted by the presence of >2 gene mutations (p = 0.024). In the analysis of clinical characteristics, hemoglobin concentration (HB) and MMR were independent factors for deep molecular response (DMR), and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found the ELTS score was the best for predicting the efficacy of TKI therapy and the Socal score was the best for predicting mutations other than BCR∷ABL.

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Section: Discussionmentioning

confidence: 99%

Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

Chen²,

Xu³

et al. 2022

Cancers

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“… 47 Although the underlying causes for anemia in CML patients and aging CML mice are not clear, it may be related to age, radiation, transplantation, therapy, and other age-related changes of bone marrow. 44 , 47 In this regard, aging mice may model human CML pathogenesis better than young mice.…”

Section: Discussionmentioning

confidence: 99%

An aging mouse model of human chronic myeloid leukemia

et al. 2021

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Chronic myeloid leukemia (CML) is an age-dependent blood malignancy. Like many other age-dependent human diseases, laboratory animal research of CML uses young mice that do not factor in the influence of aging. To understand how aging may impact animal modeling of human age-dependent diseases, we established the first aging mouse model of human CML in BALB/c mice in the advanced age defined by 75% survival. This model was developed by noncytotoxic depletion of bone marrow lineage-positive cells followed by BCR-ABL retroviral transduction and transplantation. CML developed in aging mice shared many similarities to that in young mice, but had increased incidence of anemia that is often seen in human CML. Importantly, we showed that aging of both donor hematopoietic stem cells and recipient bone marrow niche impacted BCR-ABL mediated leukemogenesis and leukemia spectrum. Optimal CML induction relied on age-matching for donors and recipients, and cross-transplantation between young and old mice produced a mixture of different leukemia. Therefore, our model provides initial evidence of the feasibility and merit of CML modeling in aging mice and offers a new tool for future studies of CML stem cell drug resistance and therapeutic intervention in which aging would be taken into consideration as an influencing factor.

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“…Anemia is relatively common in patients with chronic myeloid leukemia (CML) [ 1 ], acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS) [ 2 ]. Aplastic anemia can develop into MDS and AML, and is associated with poor outcomes [ 3 , 4 ], and can also co-occur in patients with CML [ 1 , 5 ] and AML. In addition, several case reports show that Fanconi anemia can transform into AML [ 6 – 8 ].…”

Section: Introductionmentioning

confidence: 99%

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation

Zhang,

Zhou,

et al. 2024

Stem Cell Res Ther

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Background Erythroid and myeloid differentiation disorders are commonly occurred in leukemia. Given that the relationship between erythroid and myeloid lineages is still unclear. To find the co-regulators in erythroid and myeloid differentiation might help to find new target for therapy of myeloid leukemia. In hematopoiesis, ALA (alpha lipoic acid) is reported to inhibit neutrophil lineage determination by targeting transcription factor ELK1 in granulocyte-monocyte progenitors via splicing factor SF3B1. However, further exploration is needed to determine whether ELK1 is a common regulatory factor for erythroid and myeloid differentiation. Methods In vitro culture of isolated CD34+, CMPs (common myeloid progenitors) and CD34+ CD371– HSPCs (hematopoietic stem progenitor cells) were performed to assay the differentiation potential of monocytes, neutrophils, and erythrocytes. Overexpression lentivirus of long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 transduced CD34+ HSPCs were transplanted into NSG mice to assay the human lymphocyte and myeloid differentiation differences 3 months after transplantation. Knocking down of SRSF11, which was high expressed in CD371+GMPs (granulocyte-monocyte progenitors), upregulated by ALA and binding to ELK1-RNA splicing site, was performed to analyze the function in erythroid differentiation derived from CD34+ CD123mid CD38+ CD371– HPCs (hematopoietic progenitor cells). RNA sequencing of L-ELK1 and S-ELK1 overexpressed CD34+ CD123mid CD38+ CD371– HPCs were performed to assay the signals changed by ELK1. Results Here, we presented new evidence that ALA promoted erythroid differentiation by targeting the transcription factor ELK1 in CD34+ CD371– hematopoietic stem progenitor cells (HSPCs). Overexpression of either the long isoform (L-ELK1) or the short isoform (S-ELK1) of ELK1 inhibited erythroid-cell differentiation, but knockdown of ELK1 did not affect erythroid-cell differentiation. RNAseq analysis of CD34+ CD123mid CD38+ CD371– HPCs showed that L-ELK1 upregulated the expression of genes related to neutrophil activity, phosphorylation, and hypoxia signals, while S-ELK1 mainly regulated hypoxia-related signals. However, most of the genes that were upregulated by L-ELK1 were only moderately upregulated by S-ELK1, which might be due to a lack of serum response factor interaction and regulation domains in S-ELK1 compared to L-ELK1. In summary, the differentiation of neutrophils and erythrocytes might need to rely on the dose of L-ELK1 and S-ELK1 to achieve precise regulation via RNA splicing signals at early lineage commitment. Conclusions ALA and ELK1 are found to regulate both human granulopoiesis and erythropoiesis via RNA spliceosome, and ALA-ELK1 signal might be the target of human leukemia therapy.

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Impact of anemia on the outcomes of chronic phase chronic myeloid leukemia in TKI era

Cited by 13 publications

References 9 publications

Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study

An aging mouse model of human chronic myeloid leukemia

Small-molecule α-lipoic acid targets ELK1 to balance human neutrophil and erythrocyte differentiation

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