Table 4 Summary of key findings related to drug resistance mechanisms induced by leukemia stem cells using single-cell sequencing

CML

scRNA-seq

Consistent and distinct expression of CD93 was observed on a lin − CD34 + CD38 − CD90 + CML LSC population and showed stem cell characteristics and quiescent characters. CD93 + LSCs subpopulation persisted in relapsed CML patients after the withdrawal of TKI treatment.

Showed that the CD93 is selectively and consistently expressed at the CML LSCs subpopulation, which indicates poor TKI responders.

[99]

CML

scRNA-seq; single-cell targeted mutation analysis in DNA

TGF-β and TNF-α were dysfunctional in both BCR-ABL- LSCs and BCR-ABL + LSCs. Long-term TKI treatment selected a quiescent LSC subpopulation, showing TGF-β, TNF-α, and IL-6–JAK-STAT gene enrichment. RUNX1 mutation in LSC was observed for patients entering blast crisis.

Revealed a series of prognostic markers including RUNX1 and provided indicators for TKI response.

[102]

CML

scRNA-seq

Poor imatinib responders enriched patient-specific pre-treatment stem/progenitor cells compared with responders. The stem cell feature of LSCs was present at diagnosis rather than acquired by the treatment.

Indicated that the stem cell of LSCs feature was intrinsic rather than acquired during TKI therapy in CML, revealing the need for early intervention for LSCs.

.

[103]

AML

scRNA-seq

Reprogramming of stem/progenitor-like cells into quiescent stem-like cells may provide AML with resistance during chemotherapy. Upregulation of CD52 and LGALS1 marking quiescence was observed, where CD52-SIGLEC10 interaction between QSCs and monocytes underlie the mechanism for immune evasion and resistance. Also, the LGALS1 inhibitor could help eliminate QSCs and enhance the chemotherapy in patient-derived primary AML cells.

Identified the quiescence marker, LGALS1, as a promising target for chemoresistant AML.

[104]

AML

scRNA-seq

The proliferation and self-renewal LSCs subpopulation was separated in AML, where Cd69 High LSCs were capable of self-renewal and Cd36 High LSCs were highly proliferative.

Noted that simultaneously targeting the self-renewal and proliferation in LSCs is essential for treating AML.

[105]

AML

scRNA-seq

C-Kit + B220 + Mac-1- and c-Kit + B220 + Mac-1 + LSC subpopulations were found in Setd2-/- AML, where the Mac + subpopulation was resistant to doxorubicin plus cytarabine (DA) treatment with the activation of RAS pathway.

Showed that treatments combining DA and RAS pathway targeting may improve the clinical outcome of AML.

[106]

AML

scRNA-seq

Induced by chemotherapy, AML cells depleted LSCs and entered a senescent-like phenotype. This kind of senescence was transient with increased engraftment ability. Entering the senescence-like phenotype was dependent on ATR. Post-senescence AML cells increased stem cell potential and conferred relapse.

Proposed that the stem cell feature of AML presented at relapse may be the consequence rather than the reason for relapse. Targeting the senescent-like feature by ATR may underlie therapeutic effectiveness.

[107]

AML

CITE-seq

A novel phenotype of monocytic LSC (m-LSC) was discovered, distinguished by CD34-, CD4+, CD11b-, CD14-, CD36-, driving relapse/refractory response in venetoclax-based treatment. This m-LSC is developmentally and clinically distinct from the more well-described primitive LSC (p-LSC) but can co-exist in the same AML patient. The authors found unique enrichment purine/pyrimidine metabolism selective sensitivity to cladribine in m-LSCs.

Offered insight into venetoclax-based treatment relapse and indicated that co-targeting p-LSCs and m-LSCs may be clinically important in treating AML.

[37]