EHA 2026 | Updated genomic insights in Ph+ acute lymphoblastic leukemia

Since the discovery of the Philadelphia chromosome and the identification of the BCR-ABL fusion, we learned a lot about the biology of a Ph-positive acute lymphoblastic leukemia. And now we recognize that this disease is not only solely driven by BCR-ABL, but there are a lot of cooperating genetic alterations that really shape the biology of this disease. They really impact the response to treatment and the risk of relapse. Most of these alterations have been identified during the past decade through advances in technologies. Starting from SNP array to next generation sequencing, we now have a spectrum of alterations that define specific risk of disease. The most prominent one is IKZF1, so deletions in a gene that encode for IKAROS transcription factors. And deletions of this gene together with other deletions in genes such as CDKN2A, CDKN2B, PAX5, they define the so-called IKZF1 plus status, which is associated with poor prognosis in patients, both adults and pediatric. However, genetic alterations alone do not explain the remarkable heterogeneity that we see in these leukemia subtypes. And there is evidence that the developmental state in which these alterations occur really matters. And so one of the main topics of my presentation was to highlight how the cell developmental state impacts the biology of Ph-positive ALL. And this big advance has been due to the understanding of the normal B-cell development through single cell sequencing studies. We were able last year to develop a reference map at the single cell level of normal B-cell development, where each cell state can be mapped together with the proximal lineages, such as hematopoietic stem and progenitor cells. And this is really helpful, since we can now understand better differences in developmental states across different leukemia samples. And especially in Ph-positive ALL, we now distinguish two main subgroups based on the developmental state. One, which is more immature, that is characterized by an enrichment of early common lymphoid progenitors. And one that is more differentiated, that we call committed, that is characterized by classical pro-B-cell enrichment. So these two subgroups based on developmental state really define two different diseases with different transcriptomic profiles, different genetic lesions. Although they all share BCR-ABL, they are different in terms of transcriptomic profile, collisions, and developmental state. And specifically, the multipotent subgroup is characterized by expression of myeloid signature genes, such as CEBP-alpha. And we have demonstrated that those cells are able to differentiate into myeloid progeny. So this is really important because some of those BCR-ABL subgroups have been associated with lymphoid to myeloid lineage switch. So it’s important to recognize. And actually, the current ICC classification recognizes two groups of BCR-ABL positive ALL, the so-called multilineage that is similar to the one that we call early multipotent, which is characterized by the presence of BCR-ABL also in non-lymphoid cells, such as myeloid cells or other lymphoid cells within the hematopoiesis. And the lymphoid-only group, which is instead characterized by the presence of BCR-ABL only in lymphoblasts. Of course, the presence of these two subgroups, and specifically the presence of BCR-ABL within myeloid cells creates some understanding regarding measurable residual disease because there can be some discordant results between MRD measured by NGS for immunoglobulin T-cell receptor and MRD measured by quantification of BCR-ABL transcript. And several studies have been performed to compare the two levels of MRD. And despite the positivity for BCR-ABL, negativity MRD measured by NGS for immunoglobulin T-cell receptor is the only prognostic factor based on the actual studies.Since the discovery of the Philadelphia chromosome and the identification of the BCR-ABL fusion, we learned a lot about the biology of a Ph-positive acute lymphoblastic leukemia. And now we recognize that this disease is not only solely driven by BCR-ABL, but there are a lot of cooperating genetic alterations that really shape the biology of this disease. They really impact the response to treatment and the risk of relapse. Most of these alterations have been identified during the past decade through advances in technologies. Starting from SNP array to next generation sequencing, we now have a spectrum of alterations that define specific risk of disease. The most prominent one is IKZF1, so deletions in a gene that encode for IKAROS transcription factors. And deletions of this gene together with other deletions in genes such as CDKN2A, CDKN2B, PAX5, they define the so-called IKZF1 plus status, which is associated with poor prognosis in patients, both adults and pediatric. However, genetic alterations alone do not explain the remarkable heterogeneity that we see in these leukemia subtypes. And there is evidence that the developmental state in which these alterations occur really matters. And so one of the main topics of my presentation was to highlight how the cell developmental state impacts the biology of Ph-positive ALL. And this big advance has been due to the understanding of the normal B-cell development through single cell sequencing studies. We were able last year to develop a reference map at the single cell level of normal B-cell development, where each cell state can be mapped together with the proximal lineages, such as hematopoietic stem and progenitor cells. And this is really helpful, since we can now understand better differences in developmental states across different leukemia samples. And especially in Ph-positive ALL, we now distinguish two main subgroups based on the developmental state. One, which is more immature, that is characterized by an enrichment of early common lymphoid progenitors. And one that is more differentiated, that we call committed, that is characterized by classical pro-B-cell enrichment. So these two subgroups based on developmental state really define two different diseases with different transcriptomic profiles, different genetic lesions. Although they all share BCR-ABL, they are different in terms of transcriptomic profile, collisions, and developmental state. And specifically, the multipotent subgroup is characterized by expression of myeloid signature genes, such as CEBP-alpha. And we have demonstrated that those cells are able to differentiate into myeloid progeny. So this is really important because some of those BCR-ABL subgroups have been associated with lymphoid to myeloid lineage switch. So it’s important to recognize. And actually, the current ICC classification recognizes two groups of BCR-ABL positive ALL, the so-called multilineage that is similar to the one that we call early multipotent, which is characterized by the presence of BCR-ABL also in non-lymphoid cells, such as myeloid cells or other lymphoid cells within the hematopoiesis. And the lymphoid-only group, which is instead characterized by the presence of BCR-ABL only in lymphoblasts. Of course, the presence of these two subgroups, and specifically the presence of BCR-ABL within myeloid cells creates some understanding regarding measurable residual disease because there can be some discordant results between MRD measured by NGS for immunoglobulin T-cell receptor and MRD measured by quantification of BCR-ABL transcript. And several studies have been performed to compare the two levels of MRD. And despite the positivity for BCR-ABL, negativity MRD measured by NGS for immunoglobulin T-cell receptor is the only prognostic factor based on the actual studies.

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