Is acute lymphoblastic leukemia with mature B-cell phenotype and <i>KMT2A</i> rearrangements a new entity? A systematic review and meta-analysis

Hidalgo-Gómez, Gloria; Palacio-García, Carlos Andrés; Gallur, Laura; Blanco, Adoración; Tazón-Vega, Bárbara; Saumell, Sílvia; Martínez, N. Ramírez; Murillo, Laura; Murciano, Thais; Velasco, Pablo; Bosch, Francesc; Díaz-Heredia, Cristina; Ortega, Margarita

doi:10.1080/10428194.2021.1907375

Cited by 3 publications

(5 citation statements)

References 24 publications

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“…The differing stages of arrested B-lineage differentiation may be attributable to the different instructive capabilities of different KMT2A fusions, as suggested by a reported model system 30 , in which genetically concordant human CB HSPCs were transformed into pro-B and pre-B-ALL by KMT2A-Aff1 and KMT2A-MLLT3 , respectively. A recent case review reporting the recurrent KMT2A-MLLT3 rearrangement in extremely rare mature B-ALL patients 38 also suggests an instructive preference of KMT2A-MLLT3 for B-lineage maturation. In addition, two recent DNA methylation profiling studies demonstrated relatively similar methylation profiles between KMT2A-MLLT3 and KMT2A -germline infants 39 , 40 , which may be due to the common pre-B state of KMT2A-MLLT3 and KMT2A -germline infant ALL.…”

Section: Discussionmentioning

confidence: 96%

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

et al. 2022

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KMT2A-rearranged infant acute lymphoblastic leukemia (ALL) represents the most refractory type of childhood leukemia. To uncover the molecular heterogeneity of this disease, we perform RNA sequencing, methylation array analysis, whole exome and targeted deep sequencing on 84 infants with KMT2A-rearranged leukemia. Our multi-omics clustering followed by single-sample and single-cell inference of hematopoietic differentiation establishes five robust integrative clusters (ICs) with different master transcription factors, fusion partners and corresponding stages of B-lymphopoietic and early hemato-endothelial development: IRX-type differentiated (IC1), IRX-type undifferentiated (IC2), HOXA-type MLLT1 (IC3), HOXA-type MLLT3 (IC4), and HOXA-type AFF1 (IC5). Importantly, our deep mutational analysis reveals that the number of RAS pathway mutations predicts prognosis and that the most refractory subgroup of IC2 possesses 100% frequency and the heaviest burden of RAS pathway mutations. Our findings highlight the previously under-appreciated intra- and inter-patient heterogeneity of KMT2A-rearranged infant ALL and provide a rationale for the future development of genomics-guided risk stratification and individualized therapy.

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Section: Discussionmentioning

confidence: 96%

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

et al. 2022

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“…In addition, the fusion score of BCR-ABL1 in 10 of 14 patients with CML was >0.74 ( Figure 7 E), and its fusion score in most CML cell line samples was >0.90 ( Figure 7 F). The fusion gene KMT2A-AFF1 , which was previously reported to be related to poor prognosis of pro–B-ALL 48 and occurred in subtype 4 or subtype 5 AML, was detected in 22 of 28 (78.6%) of samples of SEM (pro–B-ALL cell line) and 9 of 16 (56.3%) of samples in MV4-11 (subtype 5 AML cell line; Figure 7 G). Notably, the average fusion scores of KMT2A-AFF1 were >0.9 in SEM and MV4-11 cell lines ( Figure 7 H-I).…”

Section: Resultsmentioning

confidence: 72%

“…In addition, the fusion score of BCR-ABL1 in 10 of 14 CML patients was greater than 0.74 (Figure 7E), and its fusion score in most CML cell line samples was greater than 0.90 (Figure 7F). The fusion gene KMT2A-AFF1, which was previously reported to be related to poor prognosis of Pro-B-ALL 48 and occurred in M4 or M5 AML, was detected in 78.6% (22/28) samples of SEM (Pro-B-ALL cell line) and 56.3% (9/16) samples in MV4-11 (M5 AML cell line;…”

Section: Landscape Of Fusion Genes In Leukemia Subtypes and Cell Linesmentioning

confidence: 89%

A comprehensive landscape of transcription profiles and data resources for human leukemia

et al. 2023

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The tyrosine kinase inhibitor dasatinib is approved for Philadelphia chromosome positive leukemia, including chronic myeloid leukemia (CML). While effective and well tolerated, patients typically exhibit a transient lymphocytosis following dasatinib uptake. The underlying physiological process linking dasatinib to lymphocytosis has remained unknown to date. Here, we used a small rodent model to examine the mechanism of dasatinib-induced lymphocytosis, focusing on lymphocyte trafficking into and out of secondary lymphoid organs (SLO). Our data indicate that lymphocyte homing to lymph nodes (LN) and spleen remained unaffected by dasatinib treatment. In contrast, dasatinib promoted lymphocyte egress from spleen with kinetics consistent with the observed lymphocytosis. Unexpectedly, dasatinib-induced lymphocyte egress occurred independently of canonical sphingosine-1-phosphate-mediated egress signals. Instead, dasatinib treatment led to a decrease in spleen size, concomitant with increased splenic stromal cell contractility as measured by myosin light chain phosphorylation. Accordingly, dasatinib-induced lymphocytosis was partially reversed by pharmacological inhibition of the contraction-promoting factor ROCK. Finally, we uncovered a decrease in spleen size of CML patients who showed lymphocytosis immediately following dasatinib treatment, and this reduction was proportional to the magnitude of lymphocytosis and dasatinib plasma levels. In sum, our work provides evidence that dasatinib-induced lymphocytosis is a consequence of drug-induced contractility of splenic stromal cells.

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“…Therefore, co‐occurring CRLF2 ‐R or other BCR::ABL1 ‐like genetic abnormality does not appear to explain the few non‐ BCR::ABL1 +/like cases with IGJ+ staining. UH‐072 differed from the other KMT2A ‐R cases in lacking the characteristic CD10−, CD15+ phenotype of most KMT2A ‐R B‐ALL 37 and instead having a mature immunophenotype (Tdt‐, CD34−, CD20+, dim surface lambda light chain) as described in a minority of KMT2A ‐R B‐ALL cases 38–41 . No distinguishing features were seen between the IGJ+ and the respective IGJ− ETV6::RUNX1 and NFS cases.…”

Section: Resultsmentioning

confidence: 92%

“…UH-072 differed from the other KMT2A-R cases in lacking the characteristic CD10−, CD15+ phenotype of most KMT2A-R B-ALL 37 and instead having a mature immunophenotype (Tdt-, CD34−, CD20+, dim surface lambda light chain) as described in a minority of KMT2A-R B-ALL cases. [38][39][40][41] No distinguishing features were seen between the IGJ+ and the respective IGJ− ETV6::RUNX1 and NFS cases. We also did not identify any unifying features in IGJ+ non-BCR::ABL1+/like cases or between these cases and the BCR::ABL1+/like cases.…”

Section: F I G U R E 1 Variable Expression Of Igj Protein Inmentioning

confidence: 93%

IGJ and SPATS2L immunohistochemistry sensitively and specifically identify BCR::ABL1+ and BCR::ABL1‐like B‐acute lymphoblastic leukaemia

Gestrich,

De Lancy,

Kresak

et al. 2023

Br J Haematol

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SummaryTherapeutic management and prognostication for patients with B‐acute lymphoblastic leukaemia (B‐ALL) require appropriate disease subclassification. BCR::ABL1‐like B‐ALL is unique in that it is defined by a gene expression profile similar to BCR::ABL1+ B‐ALL rather than a unifying recurrent translocation. Current molecular/cytogenetic techniques to identify this subtype are expensive, not widely accessible, have long turnaround times and/or require an adequate liquid biopsy. We have studied a total of 118 B‐ALL cases from three institutions in two laboratories to identify surrogates for BCR::ABL1+/like B‐ALL. We report that immunoglobulin joining chain (IGJ) and spermatogenesis associated serine‐rich 2‐like (SPATS2L) immunohistochemistry (IHC) sensitively and specifically identify BCR::ABL1+/like B‐ALL. IGJ IHC positivity has a sensitivity of 83%, a specificity of 95%, a positive predictive value (PPV) of 89% and a negative predictive value (NPV) of 90%. SPATS2L staining has similar sensitivity and NPV but lower specificity (85%) and PPV (70%). The presence of either IGJ or SPATS2L staining augments the sensitivity (93%) and NPV (95%). While these findings would need to be validated in larger studies, they suggest that IGJ and/or SPATS2L IHC may be utilized in identifying BCR::ABL1‐like B‐ALL or in selecting B‐ALL cases for confirmatory molecular/genetic testing, particularly in resource‐limited settings.

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Is acute lymphoblastic leukemia with mature B-cell phenotype and KMT2A rearrangements a new entity? A systematic review and meta-analysis

Cited by 3 publications

References 24 publications

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

Multi-omics analysis defines highly refractory RAS burdened immature subgroup of infant acute lymphoblastic leukemia

A comprehensive landscape of transcription profiles and data resources for human leukemia

IGJ and SPATS2L immunohistochemistry sensitively and specifically identify BCR::ABL1+ and BCR::ABL1‐like B‐acute lymphoblastic leukaemia

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