scholarly journals IKZF1deletions Coupled with CD20 Expression Represents a Novel High-Risk Subtype in Adult B-Cell Progenitor Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4474-4474
Author(s):  
Bingqing Tang ◽  
Zhixiang Wang ◽  
Dainan Lin ◽  
Xianjun He ◽  
Zihong Cai ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Validation Cohort ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Poor Outcome ◽  
Cd20 Expression ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Genetic deletions of IKZF1 are associated with poor prognosis in B-cell acute lymphoblastic leukemia (B-ALL). Here we investigated the effect of IKZF1 deletions (IKZF1 del) plus with immunotype in adult B-ALL in PDT-ALL-2016 cohort. This cohort study involved 161 patients with B-ALL from 2016 to 2019, with detailed information about IKZF1 del and CD20 expression. Validation cohort consists N= patients from TARGET cohort. IKZF1 del was detected in 36.0% of patients with 3-year event-free survival (EFS) of 37.2±6.7% and overall survival (OS) of 51.1±7.3%, compared to IKZF1 wild-type (IKZF1 wt) with EFS 55.4±5.1% (P<0.01) and OS 74.6±4.5% (P<0.05), respectively. CD20 expression was also associated with inferior EFS than CD20-negative group (P<0.05). Furthermore, IKZF1 del coupled with CD20 expression, termed as IKZF1 del/CD20+, comprised 12.4% of patients with 3-year EFS of 25.0±9.7% compared with IKZF1 wt (P<0.05 ) and IKZF1 del/CD20- (P<0.05 ) groups, respectively. Multivariable analyses demonstrated independence of IKZF1 del/CD20+ with highest hazard ratio for EFS and OS. Furthermore, the prognostic strength of IKZF1 del/CD20+ was confirmed in TARGET validation cohort. Eighty-one patients received allogeneic hematopoietic stem cell transplantation (allo-HSCT). Notably, neither IKZF1 del(P=0.6288), CD20 (P=0.0705) or IKZF1 del/CD20 (P=0.3410) groups were identified as poor outcome in allo-HSCT cohort. Collectively, our data demonstrate that IKZF1 del/CD20+ represents a very high-risk subtype in adult B-ALL; and particularly, allo-HSCT could overcome the poor outcome of IKZF1 del and IKZF1 del/CD20+. Disclosures No relevant conflicts of interest to declare.

Mechanisms of CRLF2 Rearrangement with IGH and P2RY8 in B-Cell Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3243-3243 ◽  
Author(s):  
David M Miller ◽  
Akinori Yoda ◽  
Yuka Yoda ◽  
David M Weinstock
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Transcriptional Control ◽  
Conflicts Of Interest ◽  
Single Case ◽  
Lymphoblastic Leukemia ◽  
Receptor Gene ◽  
Great Majority ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Abstract 3243 Poster Board III-180 Introduction Precursor B-cell acute lymphoblastic leukemia (B-ALL) is the most common malignancy in children. While the great majority of these children achieve long-term remission, the disease exacts a high mortality in adults, and children with high-risk features. Fusion oncogenes such as BCR-ABL, MLL-AF4, E2A-PBX and TEL-AML1 are present in 60% of B-ALL cases. Cloning of these rearrangements has provided significant insight into the mechanisms involved in their formation. The gene alterations that affect the remaining 40% are poorly understood. We and others have recently identified CRLF2, a subunit of the thymic stromal lymphopoietin receptor, as a novel oncoprotein in B-ALL. Approximately 15% of adult and high-risk pediatric B-ALL that lack other characteristic gene rearrangements overexpress CRLF2, while leukemias with these rearrangements do not. In cases with CRLF2 overexpression, CRLF2 appears to be the driver of STAT activation, either alone or in combination with gain-of-function mutations in Janus Kinases (JAKs). CRLF2 overexpression results from rearrangements involving the CRLF2 locus, which is located in the pseudoautosomal regions on chromosomes X and Y. These rearrangements can either involve translocation with the immunoglobulin heavy chain (IGH) locus (t(X;14)(p22;q32) or t(Y;14)(p11;q32)) or interstitial deletion (del(X)(p22.33p22.33) or del(Y)(p11.32p11.32)). We sought to define the mechanisms of cleavage and repair that mediate these rearrangements. Methods For the translocations, we performed a series of polymerase chain reaction (PCR) assays to amplify junctions between IGHJ segments on chr.14 and the region upstream (i.e., centromeric) of CRLF2 on chr.X/Y. For the deletions, we used single nucleotide polymorphism (SNP) arrays and quantitative PCR to define the extent of deletions and then amplified junctions by PCR. Results We successfully amplified IGHJ/CRLF2 translocation junctions from six B-ALL with CRLF2 overexpression. Junctions involved chr.X/Y sequence between 8-16kb upstream of the CRLF2 translation start site. Five of 6 clustered near putative V(D)J recombinase recognition signal sequences (RSS). Additional evidence for involvement of the V(D)J recombinase was identified in all cases, including the presence of nontemplated nucleotides. In contrast, deletions resulted in juxtaposition of the full length CRLF2 coding sequence to P2RY8. A similar event involving t(X;12) that resulted in SOX5 translocation to P2RY8 has been described in a single case of splenic follicular lymphoma. P2RY8 is a member of the purine nucleotide G-protein coupled receptor gene family and is highly expressed in lymphocytes. Conclusion CRLF2 rearrangements result in overexpression through juxtaposition to alternate transcriptional control elements. While translocations appear to be mediated by aberrant V(D)J recombination, deletions likely involve an alternate sequence-dependent mechanism that targets downstream of the P2RY8 promoter. Disclosures No relevant conflicts of interest to declare.

B-Cell Acute Lymphoblastic Leukemia Arising in Patients with a Preexisting Diagnosis of Multiple Myeloma Is a Novel Cancer with High Incidence of TP53 Mutations

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 20-20
Author(s):  
Monique Chavez ◽  
Erica Barnell ◽  
Malachi Griffith ◽  
Zachary Skidmore ◽  
Obi Griffith ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Acute Lymphoblastic Leukemia ◽  
B Cells ◽  
B Cell ◽  
Mechanism Of Action ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Hematopoietic Stem ◽  
Tp53 Mutations ◽  
Cell Acute Lymphoblastic Leukemia

Multiple Myeloma (MM) is a malignancy of plasma cells that affects over 30,000 Americans every year. Despite advances in the treatment of the disease, approximately 12,000 American patients will still die of MM in 2019. One of the mainstays of treatment for MM is the immunomodulatory and antiangiogenic drug lenalidomide; which is used in induction therapy, maintenance therapy and treatment of relapsed disease. Although not fully elucidated, lenalidomide's mechanism of action in MM involves the drug binding to Cerebelon (CBN) and leads to the subsequent degradation of the Ikaros (IKZF1) and Aiolos (IKZF3) transcription factors (TF). These TFs play important regulatory roles in lymphocyte development. Despite lenalidomide's importance in MM treatment, several groups have reported that MM patients treated with lenalidomide rarely go on to develop B-cell acute lymphoblastic leukemia (B-ALL). The genetics and clonal relationship between the MM and subsequent B-ALL have not been previously defined. Importantly, it is not clear if the MM and B-ALL arise from the same founding clone that has been under selective pressure during lenalidomide treatment. As deletions in IKZF1 are common in B-ALL, one could hypothesize that lenalidomide's mechanism of action mimics this alteration and contributes to leukemogenesis. We sequenced the tumors from a cohort of seven patients with MM treated with lenalidomide who later developed B-ALL. These data did not show any mutational overlap between the MM and ALL samples-the tumors arose from different founding clones in each case. However, several genes were recurrently mutated in the B-ALL samples across the seven patients. These genes included TP53, ZFP36L2, KIR3DL2, RNASE-L, and TERT. Strikingly, five of the seven patients had a TP53 mutations in the B-ALL sample that was not present in the matched MM sample. The frequency of TP53 mutations in our cohort was much higher than that reported in adult de novo B-ALL patients which can range between 4.1-6.4% (Hernández-Rivas et al. 2017 and Foa et al. 2013). Utilizing CRISPR-Cas9 gene editing, we disrupted the Zfp36l2 or Actb in murine hematopoietic stem cells (HSCs) of mice with or without loss of Trp53. We performed our first transplantation experiment in which the cohorts of mice have loss of Trp53 alone, loss of Zfp36l2 alone, loss of both Trp53 and Zfp36l2, or a control knockout (KO) of Actb. To characterize the disruption of Zfp36l2 alone and in combination with Trp53 we analyzed the hematopoietic stem and progenitor cell compartments in the bone marrow of the above transplanted mice. In mice with a loss of Zfp36l2 there is a decrease in Lin- Sca-1+ c-Kit+ (LSK), short term-HSC (ST-HSC), and multipotent progenitors (MPP). This decrease was not observed in the mice with a loss of both Trp53 and Zfp36l2, where instead we noted an increase in monocyte progenitors (MP), granulocytes-macrophage progenitors (GMP), and common myeloid progenitors (CMP) cells. In this Trp53 Zfp36l2 double loss model we also noted a decrease in B220+ B-cells that was not seen in the Zfp36l2 alone. In this cohort of Trp53 Zfp36l2 loss, we characterized B-cell development through hardy fraction flow cytometry, and identified a decrease in fractions A and B/C (pre-pro and pro-B-cells, respectively) as compared to Zfp36l2 or Actb alone. As lenalidomide does not bind to Cbn in mice, we used the human B-ALL NALM6 cell line to test if treatment with lenalidomide will lead to a selective growth advantage of cells with the same genes knocked out versus wild-type control cells grown in the same culture. We hypothesize that lenalidomide treatment selectively enriched for pre-existing mutated cell clones that evolved into the B-ALL. Preliminary data in NALM6 cells with a loss of TP53 demonstrate a slight increase in cell number at day 7 compared to a RELA control. These experiments will be repeated with concurrent ZFP36L2 and TP53 mutations as well as ZFP36L2 alone. Treatment-related disease is a key consideration when deciding between different treatment options, and this project aims to understand the relationship between MM treatment and B-ALL occurrence. It may be possible to identify MM patients who are at-risk for B-ALL. For example, MM patients who harbor low-level TP53 mutations prior to lenalidomide treatment could be offered alternative treatment options. Disclosures Barnell: Geneoscopy Inc: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees. Wartman:Novartis: Consultancy; Incyte: Consultancy.

scholarly journals Aberrant GATA2 Activation in Pediatric B-Cell Acute Lymphoblastic Leukemia

2022 ◽  
Vol 9 ◽  
Author(s):  
Han Wang ◽  
Bowen Cui ◽  
Huiying Sun ◽  
Fang Zhang ◽  
Jianan Rao ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Transcriptome Sequencing ◽  
Lymphoblastic Leukemia ◽  
Myeloid Differentiation ◽  
Sequencing Data ◽  
Hematopoietic Progenitors ◽  
Hematopoietic Stem ◽  
Topologically Associating Domains ◽  
Cell Acute Lymphoblastic Leukemia

GATA2 is a transcription factor that is critical for the generation and survival of hematopoietic stem cells (HSCs). It also plays an important role in the regulation of myeloid differentiation. Accordingly, GATA2 expression is restricted to HSCs and hematopoietic progenitors as well as early erythroid cells and megakaryocytic cells. Here we identified aberrant GATA2 expression in B-cell acute lymphoblastic leukemia (B-ALL) by analyzing transcriptome sequencing data obtained from St. Jude Cloud. Differentially expressed genes upon GATA2 activation showed significantly myeloid-like transcription signature. Further analysis identified several tumor-associated genes as targets of GATA2 activation including BAG3 and EPOR. In addition, the correlation between KMT2A-USP2 fusion and GATA2 activation not only indicates a potential trans-activating mechanism of GATA2 but also suggests that GATA2 is a target of KMT2A-USP2. Furthermore, by integrating whole-genome and transcriptome sequencing data, we showed that GATA2 is also cis activated. A somatic focal deletion located in the GATA2 neighborhood that disrupts the boundaries of topologically associating domains was identified in one B-ALL patient with GATA2 activation. These evidences support the hypothesis that GATA2 could be involved in leukemogenesis of B-ALL and can be transcriptionally activated through multiple mechanisms. The findings of aberrant activation of GATA2 and its molecular function extend our understanding of transcriptional factor dysregulation in B-ALL.

scholarly journals Inotuzumab Ozogamicin Is an Effective Salvage Therapy in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia with High-Risk Molecular Features, Including TP53 Loss

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3888-3888 ◽  
Author(s):  
Xiaochuan Yang ◽  
Amber C. King ◽  
Charlene C. Kabel ◽  
Christopher J. Forlenza ◽  
Jae H. Park ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Response Rate ◽  
Lymphoblastic Leukemia ◽  
Advisory Board ◽  
Inotuzumab Ozogamicin ◽  
Ras Mutations ◽  
Molecular Features ◽  
Cell Acute Lymphoblastic Leukemia

Introduction: Adults with (w/) B-cell acute lymphoblastic leukemia (B-ALL) exhibit high rates of complete response (CR) to induction chemotherapy, but relapse is common. Inotuzumab ozogamicin (IO), an antibody-drug conjugate targeting CD22, achieves high rates of CR in patients (pts) w/ relapsed/refractory (R/R) B-ALL and is FDA-approved for R/R B-ALL in adults. It remains unknown whether cytogenetic and molecular features associated w/ decreased response rate and poor prognosis following conventional chemotherapy are associated w/ response to IO. As such, we investigated the relationship between several high-risk genetic alterations and outcome following IO treatment in pts w/ R/R B-ALL. Methods: We reviewed electronic medical records of pts of all ages w/ R/R B-ALL or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) receiving IO at Memorial Sloan Kettering Cancer Center (MSK) between January 2011 and April 2019. The primary objective was to assess whether recurrent cytogenetic or molecular features were associated w/ achievement of CR or CR w/ incomplete hematologic recovery (CRi), w/ or w/o measurable residual disease (MRD), and disease-free (DFS) and overall survival (OS) following IO. Secondary objectives included association of baseline clinical features, including central nervous system (CNS) or other extramedullary (EM) disease, w/ outcomes post-IO. MRD was defined as any unequivocal evidence of B-ALL detectable by RT-PCR (Ph+ ALL) or flow cytometry (FACS). Genomic alterations were defined by MSK IMPACT-Heme (Cheng, J Mol Diagn, 2015), FoundationOne Heme, or similar platforms. A set of selected high-risk (HR) features in Philadelphia chromosome-negative (Ph-) B-ALL was defined prior to the analysis (HR: mutations/loss of TP53, IKZF1/3, CDKN2A, CREBBP; activating RAS mutations; "Ph-like" profile). DFS and OS were computed using Kaplan-Meier methods and compared between groups using log-tank tests. Results: 32 pts (13F, 19M) w/ R/R B-ALL (n=31) or CML-LBP (n=1) treated w/ IO were identified. IO was given as monotherapy in 27 pts and w/ other systemic therapy in 5 pts (mini-hyper-CVD-like regimen, n=4; ponatinib, n=1). Median age at start of IO was 45 years (range 3-78). 10 pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). Seven and 15 pts had a history of CNS disease or other EM involvement by B-ALL, respectively, including 3 and 6 pts immediately prior to IO, respectively. Pts received a median 3 lines of salvage prior to IO, including prior CD19-targeted immunotherapy (blinatumomab and/or CAR-T cells) in 24 pts(Table 1). Among 27 pts w/ Ph- B-ALL, 12 had the selected HR features (Table 2). Five pts had Ph+ ALL (n=4) or CML-LBP (n=1) and 5/5 harbored ABL1 kinase domain point mutations (4/5 w/ T315I mutation). 22 pts had at least one successful molecular profiling panel.29 patients had initial cytogenetic studies, of whom 28 patients had evaluable karyotypes. 23 pts had best response to IO of CR/CRi (MRD-, n=15; MRD+, n=8). 9 pts had no objective response to ≥1 cycle of IO. Of the 12 Ph- pts w/ selected HR mutations, 11 achieved CR/CRi. Notably, 6/6 pts w/ TP53 mutation/deletion and 5/5 pts w/ IKZF1/3 mutations (3/3 pts w/ both TP53 & IKZF mutations) achieved CR/CRi. Both pts w/ Ras mutations and 2/3 w/ Ph-like B-ALL achieved CR/CRi. 7/11 HR responders underwent alloHCT post-IO (3 had undergone pre-IO alloHCT). Pts w/ Ph- B-ALL w/ HR mutations demonstrated similar CR/CRi rate and OS to pts w/ Ph- B-ALL w/o defined HR mutations (Fig 1A-B). In contrast, only 1/5 pts w/ Ph+ ALL achieved CR/CRi (was MRD+) and 4/5 showed persistent B-ALL. OS was superior among pts w/ Ph- vs Ph+ B-ALL post-IO (8.0 vs 1.9 months, p=0.0068, Fig 1C). Among pts w/ EM disease immediately prior to IO, 3/6 achieved CR/CRi, including CR in 1 pt w/ a cardiac mass. Median DFS was 3.2 months vs. not reached following achievement of MRD+ vs MRD- CR, respectively (p=ns, Fig 1D). Conclusions: HR molecular features associated w/ poor response to chemotherapy were not associated w/ inferior response rate and overall prognosis following IO in this small series. Notably, pts w/ Ph+ ALL (all w/ ABL1 mutations) exhibited suboptimal response, possibly as pts received IO only in advanced disease states following TKI failure. This small report supports investigation of IO in frontline therapy for pts w/ B-ALL w/ HR mutations to spare unnecessary toxicities of chemotherapy and bridge successfully to alloHCT. Disclosures King: Genentech: Other: Advisory Board ; Astrazeneca: Other: Advisory board; Incyte: Other: Advisory Board. Park:Allogene: Consultancy; Amgen: Consultancy; AstraZeneca: Consultancy; Autolus: Consultancy; GSK: Consultancy; Incyte: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Takeda: Consultancy. Geyer:Dava Oncology: Honoraria; Amgen: Research Funding. OffLabel Disclosure: Inotuzumab ozogamicin is not FDA approved for pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia.

Horner syndrome in a newly diagnosed patient with high risk precursor b-cell acute lymphoblastic leukemia

2012 ◽  
Vol 59 (2) ◽  
pp. 344-344 ◽  
Author(s):  
Thomas J. Fountaine ◽  
Brooke Miller ◽  
Yousuf M. Khalifa ◽  
Jeffrey R. Andolina
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Newly Diagnosed ◽  
Horner Syndrome ◽  
Cell Acute Lymphoblastic Leukemia

Spontaneous Mutations of Bcor and Jak1/2 genes Lead to an Aggressive Leukemia of B-1 Progenitor B Cells

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3573-3573
Author(s):  
Sheryl M Gough ◽  
Liat Goldberg ◽  
Marbin Pineda ◽  
Robert L Walker ◽  
Yuelin J Zhu ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Progenitor Cell ◽  
Conflicts Of Interest ◽  
Fusion Gene ◽  
Hot Spot ◽  
Lymphoblastic Leukemia ◽  
Hematologic Malignancies ◽  
Janus Kinase ◽  
Hematopoietic Stem

Abstract NUP98 gene fusions, generated by non-random chromosomal translocations, are associated with a wide spectrum of high risk hematologic malignancies and have been shown to alter normal hematopoietic stem and progenitor cell (HSPC) gene expression programs. A recurrent t(11;17)(p15;p13) translocation in patients with AML leads to the production of a NUP98–PHF23 (NP23) fusion gene. The consequent NP23 fusion protein retains the PHD domain, known to bind H3K4me3, and is thought to have aberrant chromatin regulation properties. We have generated a transgenic mouse model of the NUP98-PHF23 gene fusion which develops a range of hematologic malignancies, most commonly pre-T LBL and AML. However, approximately 10% of NP23 mice develop an aggressive B-1 progenitor acute lymphoblastic leukemia (pro B-1 ALL). B-1 and B-2 lymphocytes have distinct developmental pathways and are thought to represent arms of the innate and adaptive immune systems, respectively. Mature B-2 lymphocytes predominate in the peripheral circulation, and are characterized by expression of B220; whereas B-1 lymphocytes are more prevalent in the pleural and peritoneal cavities, and do not express B220. Murine B cell malignancies typically stain positive for B220, and represent transformed B-2 cells. In the present study, NP23 progenitor ALLs displayed an immunophenotype (Lin-B220- CD19+ AA4.1+) that was identical to that of the recently described B-1 progenitor cell. All B-1 progenitor ALLs exhibited clonal rearrangements of the IgH gene locus. Specifically, these rearrangements involve favored usage of 3’ VH regions, similar to observations with fetal B-1 progenitor cells, further supporting the notion that these are leukemias of B-1 progenitors. Using whole exome sequencing, we found acquired mutations in the BCL6 interacting corepressor (Bcor) gene in 5 out of 7 B-1 progenitor leukemias. The mutations were all frame shift or nonsense mutations, and were located within a 9 bp “hot spot” in Bcor exon 8. In addition, 4 of 7 cases had somatic mutations of Janus kinase 1 (Jak1) or 2 (Jak2), and 7/7 cases showed hyperphosphorylation of Stat3 or Stat5, consistent with the contention that the Jak1/2 mutations are activating mutations, and leading to a hypothesis that the NP23 pro B-1 ALLs which do not harbor Jak1/2 mutations may have acquired an unidentified mutation in the Jak-Stat pathway. Of note, Jak1/2 mutations have previously been identified in a subset of high-risk pediatric B-cell precursor ALL patients. The striking correlation between Bcor and Jak1/2 mutations, occurring specifically in a subset of NP23 leukemias, implies that these three mutations (NP23, Bcor, and Jak1/2) collaborate and provide the oncogenic setting for B-1 progenitor transformation. Disclosures No relevant conflicts of interest to declare.

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