BCR-ABL1–like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review

Jain, Sarika; Abraham, Anu

doi:10.5858/arpa.2019-0194-ra

Cited by 36 publications

(31 citation statements)

References 43 publications

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“…However, eosinophilia can be notably absent and is not a requirement for the diagnosis. Additionally, BCR-JAK2 rearrangements are sometimes identified in the new provisional entity of Philadelphia chromosome-like ALL, which are characterized by activated tyrosine kinase signaling as well as JAK/STAT signaling but lack the presence of a BCR-ABL1 rearrangement [ 19 ]. The clinical heterogeneity may be the result of both disease factors (additional mutations and subclones) as well as existing host factors (germline allele diversity).…”

Section: Discussionmentioning

confidence: 99%

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

Lap

Nassereddine

Liu³

et al. 2021

Case Reports in Hematology

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Hematological malignancies with a BCR-JAK2 rearrangement have been described only sporadically in the literature over the last three decades. Although most patients suffer from a chronic myeloid neoplasm with marked eosinophilia, the clinical presentation varies significantly and can even manifest as a lymphoid malignancy. In this case report, we present a patient with a therapy-related BCR-JAK2+ myeloid neoplasm with extensive extramedullary disease localizing in the lymph nodes. While treatment with a JAK2 inhibitor (ruxolitinib) was not able to stop disease progression, combination treatment with inhibitors of both JAK2 and BCL2 (venetoclax) resulted in disease control for over 1.5 years. Combining these two inhibitors might be strategic in these patients, not only because BCL2 is a downstream target of JAK/STAT signaling but also because BCL2 is crucial for JAK2 inhibitor resistance. The recent inclusion of JAK2-rearranged malignancies in major classification systems and guidelines emphasizes the importance of not only getting a better understanding of the clinical phenotype of these rare disorders but also of identifying alternative treatment options for patients ineligible for allogeneic stem cell transplantation. Considering the low toxicity of combination treatment with these two small molecule inhibitors, this regimen could be further explored in future studies.

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Section: Discussionmentioning

confidence: 99%

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

Lap

Nassereddine

Liu³

et al. 2021

Case Reports in Hematology

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“…Ph-like or BCR-ABL1-like ALL occurs with a frequency of about 15% in children, 21% in adolescents, and 20–24% in older adults with BCP-ALL [ 77 ]. This subtype of ALL was first described in 2009 by Mulligan and by den Boer [ 78 , 79 ] and it shows a similar gene expression profile to BCR-ABL1 ALL, despite the lack of BCR :: ABL1 fusion [ 80 ].…”

Section: Genetic Biomarkersmentioning

confidence: 99%

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Lejman

Chałupnik

Chilimoniuk

et al. 2022

IJMS

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Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies characterized by abnormal proliferation of immature lymphoid cells. It is the most commonly diagnosed childhood cancer with an almost 80% cure rate. Despite favorable survival rates in the pediatric population, a significant number of patients develop resistance to therapy, resulting in poor prognosis. ALL is a heterogeneous disease at the genetic level, but the intensive development of sequencing in the last decade has made it possible to broaden the study of genomic changes. New technologies allow us to detect molecular changes such as point mutations or to characterize epigenetic or proteomic profiles. This process made it possible to identify new subtypes of this disease characterized by constellations of genetic alterations, including chromosome changes, sequence mutations, and DNA copy number alterations. These genetic abnormalities are used as diagnostic, prognostic and predictive biomarkers that play an important role in earlier disease detection, more accurate risk stratification, and treatment. Identification of new ALL biomarkers, and thus a greater understanding of their molecular basis, will lead to better monitoring of the course of the disease. In this article, we provide an overview of the latest information on genomic alterations found in childhood ALL and discuss their impact on patients’ clinical outcomes.

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“…In older adults, severe toxicities limit the ability to administer intensive chemotherapy. In B-ALL, which accounts for 80% of ALL, two molecular subtypes, BCR-ABL + and BCR-ABL-like subgroups, are associated with high relapse rates and inferior survival in both childhood and adult B-ALL [ 3 , 4 ]. These two subtypes accounts for over 60% of adult ALL in some series [ 3 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL)

et al. 2021

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Overexpression and persistent activation of STAT5 play an important role in the development and progression of acute lymphoblastic leukemia (ALL), the most common pediatric cancer. Small interfering RNA (siRNA)-mediated downregulation of STAT5 represents a promising therapeutic approach for ALL to overcome the limitations of current treatment modalities such as high relapse rates and poor prognosis. However, to effectively transport siRNA molecules to target cells, development of potent carriers is of utmost importance to surpass hurdles of delivery. In this study, we investigated the use of lipopolymers as non-viral delivery systems derived from low molecular weight polyethylenimines (PEI) substituted with lauric acid (Lau), linoleic acid (LA) and stearic acid (StA) to deliver siRNA molecules to ALL cell lines and primary samples. Among the lipid-substituted polymers explored, Lau- and LA-substituted PEI displayed excellent siRNA delivery to SUP-B15 and RS4;11 cells. STAT5A gene expression was downregulated (36–92%) in SUP-B15 and (32%) in RS4;11 cells using the polymeric delivery systems, which consequently reduced cell growth and inhibited the formation of colonies in ALL cells. With regard to ALL primary cells, siRNA-mediated STAT5A gene silencing was observed in four of eight patient cells using our leading polymeric delivery system, 1.2PEI-Lau8, accompanied by the significant reduction in colony formation in three of eight patients. In both BCR-ABL positive and negative groups, three of five patients demonstrated marked cell growth inhibition in both MTT and trypan blue exclusion assays using 1.2PEI-Lau8/siRNA complexes in comparison with their control siRNA groups. Three patient samples did not show any positive results with our delivery systems. Differential therapeutic responses to siRNA therapy observed in different patients could result from variable genetic profiles and patient-to-patient variability in delivery. This study supports the potential of siRNA therapy and the designed lipopolymers as a delivery system in ALL therapy.

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BCR-ABL1–like B-Acute Lymphoblastic Leukemia/Lymphoma: A Comprehensive Review

Cited by 36 publications

References 43 publications

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

Combined Ruxolitinib and Venetoclax Treatment in a Patient with a BCR-JAK2 Rearranged Myeloid Neoplasm

Genetic Biomarkers and Their Clinical Implications in B-Cell Acute Lymphoblastic Leukemia in Children

Therapeutic delivery of siRNA with polymeric carriers to down-regulate STAT5A expression in high-risk B-cell acute lymphoblastic leukemia (B-ALL)

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