BCR/ABL can promote CD19+ cell growth but not render them long-term stemness

Li, Donghe; Zhao, Xuemei; Zhang, Ruihong; Jiao, Bo; Liu, Ping; Ren, Ruibao

doi:10.21037/sci.2016.11.06

Cited by 6 publications

(3 citation statements)

References 31 publications

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“…Although not yet determined, it is likely that certain subgroups of B‐ALL may be more susceptible to CD19‐negative recurrence. For Philadelphia‐positive ALL, it is suspected that the leukemic stem cells may not express CD19, leaving an untargeted leukemic population . Additionally, there are likely certain genetic drivers of the leukemia, such as KMT2A translocations, that are more susceptible to lineage switch; therefore, in these subgroups of patients, caution is warranted in using CD19‐directed therapy as a definitive therapy …”

Section: Efficacy Of Car T Cells In Clinical Trials For B‐allmentioning

confidence: 99%

“…For Philadelphia-positive ALL, it is suspected that the leukemic stem cells may not express CD19, leaving an untargeted leukemic population. 43 Additionally, there are likely certain genetic drivers of the leukemia, such as KMT2A translocations, that are more susceptible to lineage switch; therefore, in these subgroups of patients, caution is warranted in using CD19-directed therapy as a definitive therapy. 42 With the need for additional target development outside of CD19, the NCI group opened a CD22 CAR T-cell trial for pediatric and young adult patients in 2014 (NCT02315612).…”

Section: Efficacy Of Car T Cells In Clinical Trials For B-allmentioning

confidence: 99%

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The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

Annesley

Summers

Ceppi

et al. 2017

Clin Pharma and Therapeutics

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Several CAR T designs with CD19 specificity have been associated with consistent responses in clinical trials with complete remission (CR) rates ranging from 70-90%. Relevant challenges remain to be addressed, such as production time, early loss of CAR T cells, relapse due to loss of the target antigen, and prevention of severe cytokine release syndrome and neurotoxicity. This review describes constructs, clinical trial results, side effects, and future direction of CAR T-cell therapy in B-ALL.

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Section: Efficacy Of Car T Cells In Clinical Trials For B‐allmentioning

confidence: 99%

Section: Efficacy Of Car T Cells In Clinical Trials For B-allmentioning

confidence: 99%

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

Annesley

Summers

Ceppi

et al. 2017

Clin Pharma and Therapeutics

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show abstract

“…One of the main reasons leukemia is difficult to cure is that the survival of leukemia stem cells (LSCs) in the protective areas of the bone marrow (BM) constantly lead to relapse [3]. Although the BCR/ABL fusion protein is the main reason for the poor outcome in patients with Ph+ ALL, it is unable to confer the long-term stemness of committed B-lymphoid progenitors [4]. In chronic myeloid leukemia (CML), BCR/ABL fusion protein induces the expression of interleukin 6 (IL-6), a pleiotropic cytokine and creates a hospitable micro-environment for leukemia to develop and sustain the stemness of LSCs [5].…”

mentioning

confidence: 99%

miR-451a induced apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells by targeting IL-6R

Jiang

Chen

Huang

et al. 2018

neo

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Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is the most fatal leukemia due to the BCR/ABL fusion protein. This fusion protein can induce interleukin 6 (IL-6) expression in leukemia stem cells (LSCs) which sustain stemness by binding IL-6R and activating the Janus kinase (JAK)/signal transducer and activator of the transcription (STAT) pathway. IL-6R was one of the targets of miR-451a down-regulated in LSCs by BCR/ABL. We investigated the relationship between miR-451a, IL-6R, and BCR/ABL in Ph+ ALL and created a strategy to treat this disease. The expression levels of miR-451a and BCR/ABL of Ph+ ALL patients were examined by real-time quantitative polymerase chain reaction (RT-qPCR) and serum IL-6 was tested by enzyme-linked immunosorbent assay. Ph+ ALL cell line SUP-B15 and Ph− ALL cell line Nalm-6 were treated with miR-451a mimic and inhibitor, respectively; proliferation rate was assessed by CCK-8, apoptosis rate was tested by Annexin/PI and the expression levels of Bcl-XL, Bax, cyclin D2 and c-myc were examined by qPCR and western blot (WB). The levels of STAT3, p-STAT3, JAK2, and p-JAK2 were tested by WB. We found that BCR/ABL was inversely related to miR-451a and positively related to IL-6 in Ph+ ALL. MiR-451a inhibited the proliferation of SUP-B15 through the apoptosis pathway. The oncogene c-myc was down-regulated by miR-451a. We confirmed that miR-451a could target IL-6R and inhibit activation of JAK and STAT3. In conclusion, miR-451a is down regulated in Ph+ ALL and increasing the expression levels of miR-451a in leukemia cells can increase the potential of curing this disease.

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Chimeric antigen receptor modified T‐cells for cancer treatment

Xiao¹,

Wang²,

Han³

2018

Chronic Diseases and Translational Medicine

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T cells engineered with the chimeric antigen receptor (CAR) are rapidly emerging as an important immunotherapy for hematologic malignancies. The anti-cluster of differentiation (CD)19 CAR-T cell therapy has been remarkably successful against refractory/relapsed acute lymphoblastic leukemia (ALL), and a complete remission rate as high as 90% was observed, in both children and adults. Although the achievement of clinical efficacy using CAR-T cell therapy for solid tumors has encountered several obstacles that were associated with the multiple mechanisms contributing to an immunosuppressive microenvironment, investigators are exploring more optimized approaches to improve the efficiency of CAR-T in solid tumors. In addition, cytokine release syndrome (CRS) and neurotoxicity following CAR-T cell therapy can be severe or even fatal; therefore, the management of these toxicities is significant. Herein, we briefly review the structure of CAR-T and some novel CAR designs, the clinical application of CAR-T cell therapies, as well as the assessment and management of toxicities.

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BCR/ABL can promote CD19+ cell growth but not render them long-term stemness

Abstract: Conclusions: These studies suggest that BCR/ABL is unable to confer the long-term stemness to committed B-lymphoid progenitors and imply that CD19 chimeric antigen receptor (CAR) modified T cell therapy may not be effective in eradicating LSCs in BCR/ABL + B-ALL.

Cited by 6 publications

References 31 publications

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

The Evolution and Future of CAR T Cells for B‐Cell Acute Lymphoblastic Leukemia

miR-451a induced apoptosis of Philadelphia chromosome-positive acute lymphoblastic leukemia cells by targeting IL-6R

Chimeric antigen receptor modified T‐cells for cancer treatment

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