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Cytogenetic characterization of the karyotype at the Day 180. a G-banded karyotype showing the 46,XY,t(1;9)(q23;q34),inv(2)
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Recently, RCSD1 was identified as a novel gene fusion partner of the ABL1 gene. The RCSD1 gene, located at 1q23, is involved in t(1;9)(q23;q34) translocation in acute B lymphoblastic leukemia. Here we describe RCSD1-ABL1-positive B-cell acute lymphoblastic leukemia (ALL) followed by rapid clonal evolution exhibiting three rare reciprocal translocat...
Citations
... 3 Ph+ ALL, TKIs have demonstrated efficacy. Previous research has shown that imatinib and dasatinib can induce remission and eliminate minimal residual disease in patients with ABL-class fusion who exhibit an inadequate response to chemotherapy [5,[21][22][23][24]. ...
Fusion genes play a crucial role in the development of Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL). Timely and accurate determination of malgenic fusion transcripts that cause Ph-like ALL is essential for guiding treatment decisions. However, due to the complexity of possible gene fusion combination of Ph-like ALL, prevailing molecular diagnostic methods for Ph-like ALL are inefficient and lack of standardization, resulting in a slow diagnostic process. We introduce Partial Anchored Capture and Long-Read Sequencing (PACLseq), a nanopore-sequencing-technology-based approach, which enables fast stand-alone identification of fusion genes with a mere 10ng of input RNA. With extensive testing using BCR-ABL1 standards and 47 clinical samples to validate the efficacy of PACLseq, we demonstrated that PACLseq performs excellently in target region coverage and fusion gene detection accuracy, achieving a sensitivity of 93.33% and specificity of 100%. These findings highlight the reliability and versatility of PACLseq as a streamlined method for the clinical diagnosis of Ph-like ALL. By offering rapid and accurate fusion gene detection, PACLseq has the potential to significantly improve diagnostic efficiency, facilitate timely treatment decisions, and enhance patient outcomes in the management of Ph-like ALL.
... 27,34 There is significant anecdotal evidence that imatinib and dasatinib can induce remissions and clear MRD in patients with Ph-like ALL and ABL-class fusions that have responded poorly to chemotherapy. 20,29,32,34,46 Based on these factors, there is strong interest in testing TKI therapy in this highrisk ALL subtype. Clinical experience in Ph 1 ALL has established that imatinib or dasatinib can be added safely to combination chemotherapy regimens. ...
Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL; also referred to as BCR-ABL1-like ALL) is a high risk subset with a gene expression profile that shares significant overlap with that of Philadelphia chromosome positive (Ph(+)) ALL and is suggestive of activated kinase signaling. While Ph(+) ALL is defined by BCR-ABL1 fusion, Ph-like ALL cases contain a variety of genomic alterations that activate kinase and cytokine receptor signaling. These alterations can be grouped into major subclasses that include ABL-class fusions involving ABL1, ABL2, CSF1R, and PDGFRB that phenocopy BCR-ABL1, and alterations of CRLF2, JAK2, and EPOR that activate JAK/STAT signaling. Additional genomic alterations in Ph-like ALL activate other kinases including BLNK, DGKH, FGFR1, IL2RB, LYN, NTRK3, PDGFRA, PTK2B, TYK2, and the RAS signaling pathway. Recent studies have helped to define the genomic landscape of Ph-like ALL and how it varies across the age spectrum, associated clinical features and outcome, and genetic risk factors. Pre-clinical studies and anecdotal reports show that targeted inhibitors of relevant signaling pathways are active in specific Ph-like ALL subsets, and precision medicine trials have been initiated for this high risk ALL subset.
... There are preclinical studies and case reports [67][68][69][70] 77,78 ; however, the experience of using chemotherapy in conjunction with TKI in the Ph+ ALL setting supports the safety of such combination. Notably, patients with KD-ALL carrying the NUP214-ABL1 translocation were reported to be TKI sensitive when the leukemia phenotype was either that of B-or T-cells [79][80][81][82][83] . ...
Recent comprehensive genetic studies revealed numerous genetic aberrations underlying a group of high-risk leukemias that share a specific activated kinase gene expression pattern. These ALLs were first recognized by the expression profile similar to that of Philadelphia chromosome positive ALL and currently can be sub-classified by the main aberrantly activated kinase in the leukemic cells. We herein review the biological mechanisms and diagnostic and clinical challenges presented by these leukemias.
... The t(9;22)(q34;q11) involving the BCR-ABL1 fusion gene has been implicated in B-ALL and is associated with a poor prognosis (Huret, 1997). Another case reported by Inokuchi et al. had a t(1;9)(q23;q34) with confirmed involvement of RCSD1 and ABL1, which was implicated in rapid clonal evolution that gave rise to rare abnormalities, including a der(19)t(17;19)(q21;p13.3), possibly involving TCF3 and HLF (Inokuchi et al., 2011). A case found by Inukai et al. that was positive for TCF3-HLF fusion by RT-PCR also had +8, +18, +21, +21, and +22 as secondary abnormalities (Table 1) (Inukai et al., 2011). ...
TCF3 (19p13.3) abnormalities are relatively common in B-cell acute lymphoblastic leukemia (B-ALL). The t(1;19)(q23;p13) involving
PBX1 is the most common of these rearrangements. The t(17;19)(q22;p13.3), resulting in the TCF3-HLF fusion gene, is also seen in
B-ALL and is associated with an extremely poor prognosis. Herein, we present the case of a 25-year-old male diagnosed with B-ALL
whose initial karyotype showed a t(17;19)(q22p13.3). FISH confirmed TCF3 involvement and also revealed a 5’ IGH deletion. After
treatment, the patient relapsed, at which point conventional cytogenetic studies showed a t(17;19), loss of the 5’ IGH region, and a
t(3;10) not seen in initial studies. After hematopoietic stem cell transplantation, the patient relapsed again, at which point conventional
cytogenetic studies showed a complex karyotype with t(17;19), t(1;9)(p13;p13), and structural anomalies involving chromosomes 5, 7, and
14, but no IGH abnormalities by FISH. The t(1;9) has been shown to involve PAX5, which plays numerous regulatory roles in B-cell
differentiation. Other PAX5 rearrangements have been detected in B-ALL cases of young adults and adolescents, but with unclear
clinical significance. To the best of our knowledge, this is the first reported case of t(17;19)-ALL with concomitant 5’ IGH deletion and
t(1;9)(p13;p13) potentially involving PAX5, albeit at different time points in disease progression. This case provides insight into the clonal
evolution of t(17;19)-ALL and the potential involvement of PAX5 and IGH aberrations in the evolution of this malignancy.
... t(1;9)(q24;q34). Detailed clinical, morphologic, and cytogenetic correlations have only been described in the literature for two cases of B-cell ALL with confirmed RCSD1-ABL1 fusion [6, 7]. In our patient, comprehensive cytogenetic and molecular characterization including Chromosomal Microarray Analysis (CMA) allowed showing association of the RCSD1-ABL1 fusion with the IKZF1 gene deletion, which is known as an adverse prognostic marker in B-ALL. ...
... We describe a patient with B-cell ALL associated with a particularly rare translocation affecting the ABL1 gene, t(1;9)(q24;q34). This translocation involves the RCSD1 gene at 1q21 and has previously been described in only four patients and confirmed by cytogenetic or molecular methods only in two patients6789. The unusual feature of the RCSD1/ABL1 fusion relative to other ABL1 rearrangements is that the N-terminal portion of the RCSD1 gene is fused to ABL1 starting from exon 4, while the other ABL1 fusion products also contain ABL1 exons 2 and 3 [7]. ...
The
RCSD1
gene has recently been identified as a novel gene fusion partner of the
ABL1
gene in cases of B-cell Acute Lymphoblastic Leukemia (B-ALL). The
RCSD1
gene is located at 1q23 and
ABL1
is located at 9q34, so that the RCSD1-ABL1 fusion typically arises through a rare reciprocal translocation t(1;9)(q23;q34). Only a small number of RCSD1-ABL1 positive cases of B-ALL have been described in the literature, and the full spectrum of clinical, morphological, immunophenotypic, and molecular features associated with this genetic abnormality has not been defined. We describe extensive genetic characterization of a case of B-ALL with RCSD1-ABL1 fusion, by using conventional cytogenetic analysis, Fluorescence In Situ Hybridization (FISH) studies, and Chromosomal Microarray Analysis (CMA). The use of CMA resulted in detection of an approximately 70 kb deletion at 7p12.2, which caused a disruption of the
IKZF1
gene. Deletions and mutations of
IKZF1
are recurring abnormalities in B-ALL and are associated with a poor prognosis. Our findings highlight the association of the deletion of
IKZF1
gene with the t(1;9)(q24;q34) and illustrate the importance of comprehensive cytogenetic and molecular evaluation for accurate prediction of prognosis in patients with B-cell ALL.
... Encouraging data on cell lines and human leukemic cells expressing ABL1, ABL2, CSF1R and PDGFRB fusions showed sensitivity in vitro to tyrosine kinase inhibitors; while EPOR and JAK2 rearrangements were sensitive to JAK2 inhibitors [66,78]. Moreover, preliminary clinical data showed sensitivity of the PDGFRB or ABL1 fusions to tyrosine kinase inhibitors [79][80][81]. Whether Ph-like ALL patients with poor initial treatment response can be salvaged with MRD-based riskdirected therapy [82] or not [77] might depend on the Ph-like definition and different therapeutic protocols. However, independently on the Ph-like ALL definition, the identification of genomic alterations that activate a limited number of signaling pathways, targetable with clinically approved tyrosine kinase or JAK2 inhibitors, highlight the need for trials to assess whether adding new target drugs to current therapy will improve the survival of patients with this type of leukemia. ...
With current treatment regimens, survival rates for acute lymphoblastic leukemia (ALL) have improved dramatically since the 1980s, with current 5-year overall survival rates estimated at greater than 85%. This success was achieved, in part, through the implementation of risk-stratified therapy. Nevertheless, for a subgroup of patients (15–20%) with newly diagnosed ALL who will ultimately relapse, traditional risk assessment remains inadequate. The risk of relapse may be estimated on the basis of diagnostic features or early treatment response findings. Further progress in this field may thus come from refinement of predictive factors for relapse and treatment adaptation and from the identification of biological subsets of ALL patients who could benefit from specific target therapies. This article summarizes the aspects associated with the identification of predictive factors for relapse in childhood ALL and options available for prevention of disease recurrence.
... Two other cases of B-cell ALL associated with a RCSD1-ABL1 fusion gene were reported in the literature. Inokuchi et al. 3 described a 31-year-old man with t(1;9)(q24;q34) in whom imatinib and dasatinib, combined with dexamethasone, achieved transient clinical effects. Leukemic cells rapidly became refractory to the treatment following the subsequent development of more cytogenetic abnormalities and the patient deceased 6 months following diagnosis. ...
... Leukemic cells rapidly became refractory to the treatment following the subsequent development of more cytogenetic abnormalities and the patient deceased 6 months following diagnosis. 3 Roberts et al. 4 reported a 15-year-old male in whom RNA-seq analysis showed a RCSD1-ABL1 fusion. No cytogenetic and clinical data were available. ...
Leukemia is one of the leading journals in hematology and oncology. It is published monthly and covers all aspects of the research and treatment of leukemia and allied diseases. Studies of normal hemopoiesis are covered because of their comparative relevance.
Acute lymphoblastic leukemia (ALL) with fusions of ABL-class tyrosine kinase genes other than BCR::ABL1 occurs in approximately 3% of children with ALL. The tyrosine kinase genes involved in this BCR::ABL1-like (Ph-like) subtype include ABL1, PDGFRB, ABL2, and CSF1R, which each have up to ten described partner genes. ABL-class ALL resembles BCR::ABL1-positive ALL by a similar gene expression profile, a poor response to chemotherapy, and sensitivity to tyrosine kinase inhibitors (TKIs). There is a lack of comprehensive data regarding TKI sensitivity for the heterogeneous group of ABL-class ALL. We observed variability in TKI sensitivity both within and amongst each ABL-class tyrosine kinase gene subgroup. We showed that ALL samples with fusions of any of the four tyrosine kinase genes were relatively sensitive to imatinib. In contrast, PDGFRB-fused ALL samples were less sensitive to dasatinib and bosutinib. Variation in ex vivo TKI response within the subset of samples with the same ABL-class tyrosine kinase gene was not associated with ALL immunophenotype, 5' fusion partner, the presence or absence of the Src-homology-2/3 domains, or deletions of IKZF1, PAX5, or CDKN2A/B. In conclusion, the tyrosine kinase gene involved in ABL-class ALL is the main determinant for TKI sensitivity and is relevant for specific TKI selection.
Purpose:
Philadelphia-like (Ph-like) B-cell ALL is a high-risk subtype of B-cell ALL that shares a gene expression profile with Ph-positive ALL, but without a BCR::ABL1 fusion. A subgroup of these patients have fusions or rearrangements involving genes such as ABL1, ABL2, PDGFRβ, JAK2, and EPOR, some of which are potentially sensitive to tyrosine kinase inhibitors (TKIs). Prompt identification of these genetic aberrations are important for prognostication and treatment decisions.
Patients and methods:
We performed a retrospective review of patients with B-cell ALL treated at MD Anderson Cancer Center to identify recurrent genetic fusions commonly seen in Ph-like ALL and focus on patients treated with TKI.
Results:
We identified 23 patients with recurrent genetic fusions commonly seen in Ph-like ALL; 14 had ABL class fusions (eight ABL1, one ABL2, and five PDGFRβ) and nine had JAK2 class fusions (five JAK2 and four EPOR). Notably, several of these fusions were cryptic by conventional cytogenetics and fluorescent in situ hybridization (FISH) assays and identified only by multiplex fusion assay. Thirteen of these 23 patients received a TKI as part of their treatment; this included ABL1 fusion (n = 8), PDGFRβ fusion (n = 4), and EPOR fusion (n = 1). All four patients with ABL1 fusions who received TKI with induction chemotherapy are alive in first remission.
Conclusion:
Understanding the genomics of B-cell ALL is important for disease prognostication and for precise treatment planning. Besides conventional cytogenetics and directed FISH testing, multiplex fusion assays can help identify recurrent chromosomal translocations that are seen in patients with Ph-like ALL. Early initiation of TKI appears beneficial; larger studies are required to fully understand the benefit of TKI and to design rational combination therapies for these patients.
Introduction
(Ph‐like) ALL is a subset of leukemia which has a gene expression profile similar to Ph+disease, but without the presence of BCR‐ABL1 translocation.
Case description
We reported an exceptional case of a child with relapsed Ph‐like ALL with IKZF1 gene deletion treated with high‐dose ruxolitinib as monotherapy, after multi‐agent chemotherapy. He remains in continued MRD‐negative leukemia remission with full donor chimerism at 12 months post‐HSCT.
Discussion
The circumstance that makes our case featured is the usage of ruxolitinib as monotherapy. This report, we believe, is a pioneering report for a frequent disease with a high risk of failure for the outcome.
