Minimal Residue of Leukemic Stem Cells and Therapeutic Resistance in Acute Myeloid Leukemia View PDF

*Gayatri Devi V
Department Of Biochemistry, Gitam Institute Of Science, Gitam Institute Of Science, GITAM University, Vishakapatnam, India

*Corresponding Author:
Gayatri Devi V
Department Of Biochemistry, Gitam Institute Of Science, Gitam Institute Of Science, GITAM University, Vishakapatnam, India
Email:gayatri.varikuti@gmail.com

Published on: 2022-03-28

Abstract

Acute Myeloid Leukemia (AML) is characterized by the clonal growth of undifferentiated myeloma progenitor cells, which leads to hematopoiesis and bone marrow failure (Figure 1) [1]. Even though most newly diagnosed AML patients attain morphological full remission following aggressive induction treatment, recurrence rates remain substantial [2]. Cancer is caused by somatically acquired driver mutations, which account for the biological and clinical complexity of diseases. Cancer categorization based on cause is expected to be robust, repeatable, and therapeutically meaningful. This is already visible in AML, where a progressive transition from a morphological categorization system to one that informs causal genetic mutations has occurred [3]. The cause of recurrence has been discovered as treatmentresistant leukemia cells comprising leukemia stem cells (LSCs), known as a minimal residual disease (MRD). Relapse is induced by treatmentresistant leukemia cells with unique gene expression profiles linked with stem less, according to the notion of cancer stem cells [4]. When these drug-resistant cells are detected early, patients can be assigned to salvage therapy or clinical trials before their AML relapses. The idea of identifying molecular MRD after therapy to predict disease relapse in AML patients has been examined, although molecular MRD evaluation is not extensively used in clinical practice. Next-generation sequencing frequently enables the thorough and simultaneous identification of patient-specific somatic mutations during diagnosis and treatment [5]. AML has developed as a complicated, dynamic disease because of whole genome sequencing. There are multiple leukemia genes, most of which are seldom altered, and patients frequently have more than one driver mutation [6]. Many competing clones coexist at any given moment while the disease progresses [7,8]. These findings demonstrate the biological intricacy of AML, although it is unclear how they may impact clinical management. For patients diagnosed with AML, who are 75 years of age or have comorbidities that prevent the administration of traditional intensive chemotherapy, durable remission was shown in the phase III clinical study. The combination of venetoclax and the hyperventilating drug azacitidine has become the standard treatment. Even following therapy with a hyperventilating drug, older people with AML have a dismal prognosis. Azacitidine in combination with venetoclax has demonstrated potential effectiveness. The investigation of leukemia genes in three clinical trials of intense AML treatment, with the recognition that the AML landscape of older individuals may be underrepresented. The structure of driver mutations indicates non-overlapping patient categories, allowing for comprehensive genomic categorization of AML. In contrast to the subclass, we will investigate gene and gene occurrence patterns, as well as how so compound genotypes relate to clinical outcomes. Azacitidinevenetoclax, decitabine-venetoclax, and low-dose cytarabine-venetoclax are currently conventional treatments for elderly or physically impaired patients diagnosed with AML. Even though these combinations are often utilized in patients with relapsed or refractory AML (RR-AML), clinical and genetic determinants of response and survival in RR-AML were shown to be 2%. The total response rate, including morphological leukemia-free status, was 31%. When azacytidine-venetoclax was used instead of low-dose cytarabine-venetoclax, the response rate was greater (9% vs. 15%; P= 0.008). NPM1 mutations were related to better response rates, whereas TP53, KRAS/NRAS, and SF3B1 mutations were associated with poor overall survival. Several processes determine the reference phenotypic expression and its plasticity, as well as the genetic modifications and gene mutations that influence it. In many metabolic and gene expression patterns that make up the patient’s remarkable heterogeneity of leukemia cells. The interplay between leukemia cells. and extra-tumor factors known as the tumor microenvironment adds to the complication [9].

Keywords

Acute Myeloid Leukemia, Cancer, Leukemia Stem Cells

Methods

There are many different cell morphologies and lymphatic activity in cells. Hematopoietic stem cells (HSCs), which are at the top of the hematopoietic organization hierarchy, are the source for most of these cells. These HSCs are distinguished by their ability to self-renew and sustain the local HSC population. Additionally, a variety of progenitor cells are produced, which multiply and develop into adult blood and immune cells. Most HSCs remain inactive or in protracted cell cycle quiescence in the steady state but return to the G0 phase to maintain their long-term function, a process known as quiescence [10,11]. HSCs are often thought to form a unique, homogenous population’s lives in a hypoxic bone marrow microenvironment known as the niche. Song, first postulated in 1978, which is today acknowledged as a sophisticated network that offers the chemical pathways and physical interactions required for the localization, upkeep, and differentiation of HSC [11]. Further mutations can augment the growth advantage, resulting in various subclones, like branching development, lead to the establishment of separate phylogenetic lineage trees in the tumor. Gene mutations, epigenetic changes that result in specific gene expression programs, and metabolic circumstances that influence the patient’s leukemia cell heterogeneity are some of the elements that characterize the LSC phenotype and its flexibility. The interplay between leukemia cells and extra-tumor factors known as the tumor microenvironment adds to the complication [9].

Leukemia is Re-initiated by Leukemic Stem Cells

Self-renewal in clonal in vivo population tests can be used to functionally identify stem cells [12]. AML is an outstanding example of a disease where self-renewal ability is assessed in xenotransplantation experiments, in which LSC grafts from uncompromising recipient mice develop leukemia [13]. Engraftment and cancer potential were restricted to the CD3CD38- fraction after flow sorting, showing that AML is structured into a hierarchical structure with CD3CD38- cancer cells at the top [14]. The potential of xenografts to halt even uncommon relapses. Appropriate LSCs enable the exploration of widespread treatment resistance and treatment strategies. Leukemic cells that can proliferate were shown to be momentarily dormant in the G0 phase of the cell cycle in NSG mice. An unusual population of quiescent longterm leukemia-initiating cells with significant self-renewal potential and very low proliferation rates was found after repeated implantation [15]. The identification of diverse relapse patterns highlights the need for more effective methods (such as single cell multiplexing) to track complex evolutionary processes. Future clinical studies aimed at tackling LSC-mediated disease should consider the history of AML in particular individuals. Treatment resistance and recurrence are also possible outcomes. It is critical to incorporate innovative medicines that target features to avoid AML recurrence.

Drug Resistance Mechanisms and Weaknesses in Leukemic Stem Cells

Resistance to Chemotherapeutic Agents

LSC is assumed to be resistant to nonproliferation treatments by nature. This is linked to their capacity to enter transitory quiescent, resting, and senescent phases, and it is assumed to mediate a variety of processes, including resistance to DNA damage [16,17]. AML cells can adopt a senescence-like resistance phenotype with great metastatic potential to survive and replenish leukemia, according to a recent study [18]. It has been shown that the temporary phenotype of AML cells occurs without the involvement of their stem cells and that the recurrence of AML with higher stem cell potential is caused by these cells. Additionally, it has been shown that chemotherapy alters the LSC landscape, resulting in temporary LSC stages with dynamic treatment resistance traits while AML is being treated. Targeting unique LSC states is challenging because of their adaptability, likelihood to be patientspecific, and potential phenotypic plasticity, which may potentially affect the expression of cell surface markers. They were thought to be dynamic, transient, and reversible stages. As a result, LSC targeting using surface markers would continue to have an impact on LSC clone removal. MYC is a transcription factor that governs saturated metabolic features, such as the balance of tranquility and multiplication of stem cells [19]. HSCs live in a niche, which is a very particular bone marrow habitat. HIF1 regulates the expression of genes in these hypoxic niches, including CXCR, it is further down regulated on the LSCs’ membrane [20]. 

Signatures of Leukemic Stem Cells and Therapeutic Targets

In functionally characterized LSCs, gene expression analysis showed that these cells exhibit a transcription profile resembling that of HSCs and that stemless-related gene expression programs are highly predictive of response to conventional AML therapy [21]. Several genes in that sensitive (17-gene signature) transcription pathway produced an LSC17 score, which may be used to predict clinical outcomes [11]. Proteins with the subdomain and extra-terminal motif (BET) that control the synthesis of MYC, as well as Brd, a BET family protein, suggest potential therapeutic targets. SC-derived BET inhibitor resistance, on the other hand, relates to transcription plasticity, including medications targeting genetics and metabolic states or immunosuppression, and can remove relapse-associated LSC. Inhibiting miR-126, a micro-RNA that controls the PI3K-Akt-mTOR pathway, for example, has been demonstrated to reduce LSC activity. PARP1 is an enzyme that utilizes NAD to transfer ADP-ribose to other proteins and is involved in various physiological functions such as DNA repair and gene control. The pharmacological suppression of PARP1 (by talazoparib) increases the re-expression of NKG2DL on the surface of LSCs, rendering these cells vulnerable to NK cell control in vivo. PARP1 suppresses NKG2DL expression [22]. 

Methodological Advancements and their Implications for Transnational Research in AML

Computed tomographic cell viability was used to annually  analyze  bone marrow aspirate samples at diagnosis and, if necessary, at recurrence. We looked at molecular determinants of response and illness progression trends. Chromosomal and genomic data were retrieved from medical records and manually filtered for accuracy using LeukNLP software (J.G.). Novel approaches now allow single-cell identification of complicated heterogeneous cell mixtures. However, methods based on bulk sample mass spectrometers and metabolic flux analyses need a large number of cells, despite the fact that it is becoming clear that dynamic metabolic variations are crucial for LSCs function and treatment resistance. They are frequently unavailable to patients; in particular, when investigating smaller sub-populations such as LSCs, the field requires improved high-resolution single-cell approaches. This technological advancement also opens up new avenues for studying unusual CH clones in the detection and characterization of residual, therapy-resistant, relapse-initiating leukemia cells, including LSCs, in MRD patients as well as the preleukemic condition. The 4-year relapse rate, relapse-free survival, and overall survival were the study’s end goals.

Conclusion

Venetoclax-based combination treatment was used to treat patients with RR-AML. Azacitidine-venetoclax was used more frequently than decitabine-venetoclax (1% vs. 23%), and nearly a third of the patients received low-dose cytarabine-venetoclax. Many decitabine-venetoclax individuals (80%) got decitabine on a 5-day schedule, whereas 20% received decitabine on a 10-day schedule. AML is a genetically diverse disease defined by a complex network of genetically unique subclones emerging from evolutionary branching including a dominant clone. A unique, non-genetically driven cell differentiation hierarchy was formed by cells inside another genetically related sub-copy, each of which had its own clone-specific chemical fingerprints. The entity  possesses inherent resistance mechanisms such as phenotypic variation, dormancy, and senescence. Targeted therapeutic techniques that particularly address LSCs features are gradually supplementing or replacing traditional chemotherapy. For patients who have relapsed or are resistant to therapy, as well as those who have just been diagnosed and who are old or have other comorbidities, venetoclax-azacitidine is a viable therapeutic choice. The molecular basis of treatment success and resistance in this situation must be investigated and clarified because this combination targets at least certain LSCs. Venetoclaxazacytidine has impressive response rates, but it is not curative because LSC has molecular and metabolic plasticity that is resistant to BCL-2 inhibition. (i.e., strong expression of MCL-1 or BCL-xL). Relevantly, while venetoclax-azacytidine effectively targets at least some LSCs, it may not target all of them in both intra- and inter-patient settings; surviving LSCs are recurrence agents that may provide new ways to monitor relapses. Identifying and pursuing therapy-resistant cells with leukemia population in upcoming clinical trials resistance phenotype LSC-targeting medications being used into first-line treatment, is crucial for avoiding AML relapse and improving clinical outcomes in the future. This approach may result in decreased recurrence and cure rates in AML patients.

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