STAT5 is activated in a broad spectrum of human hematologic malignancies. We addressed whether STAT5 activation is necessary for the myelo- and lymphoproliferative disease induced by TEL/JAK2 using a genetic approach. Whereas mice transplanted with bone marrow transduced with retrovirus expressing TEL/JAK2 develop a rapidly fatal myelo- and lymphoproliferative syndrome, reconstitution with bone marrow derived from Stat5ab-deficient mice expressing TEL/JAK2 did not induce disease. Disease induction in the Stat5a/b-deficient background was rescued with a bicistronic retrovirus encoding TEL/JAK2 and Stat5a. Furthermore, myeloproliferative disease was induced by reconstitution with bone marrow cells expressing a constitutively active mutant, Stat5a, or a single Stat5a target, murine oncostatin M (mOSM). These data define a critical role for Stat5a/b and mOSM in the pathogenesis of TEL/JAK2 disease.

Constitutive activation of tyrosine kinases, such as the BCR͞ABL fusion associated with t(9;22)(q34;q22), is a hallmark of chronic myeloid leukemia (CML) syndromes in humans. Expression of BCR͞ ABL is both necessary and sufficient to cause a chronic myeloproliferative syndrome in murine bone marrow transplantation models, and absolutely depends on kinase activity. Progression of CML to acute leukemia (blast crisis) in humans has been associated with acquisition of secondary chromosomal translocations, including the t(7;11)(p15;p15) resulting in the NUP98͞HOXA9 fusion protein. We demonstrate that BCR͞ABL cooperates with NUP98͞HOXA9 to cause blast crisis in a murine model. The phenotype depends both on expression of BCR͞ABL and NUP98͞HOXA9, but tumors retain sensitivity to the ABL inhibitor STI571 in vitro and in vivo. This paradigm is applicable to other constitutively activated tyrosine kinases such as TEL͞PDGF␤R. These experiments document cooperative effects between constitutively activated tyrosine kinases, which confer proliferative and survival properties to hematopoietic cells, with mutations that impair differentiation, such as the NUP98͞HOXA9, giving rise to the acute myeloid leukemia (AML) phenotype. Furthermore, these data indicate that despite acquisition of additional mutations, CML blast crisis cells retain their dependence on BCR͞ABL for proliferation and survival. Chronic myeloid leukemia (CML) syndromes in humans are phenotypically characterized by leukocytosis with normal maturation and differentiation of myeloid lineage cells. Cloning of recurring chromosomal translocations associated with the CML phenotype has invariably identified constitutively activated tyrosine kinases that are expressed as a consequence of the translocation. The most common of these is the t(9;22)(q34;q22) associated with the BCR͞ABL fusion transcript (1). Other examples include the t(5;12)(q33;p13), t(9;12)(q34;p13), t(9;12)(p24;p13), and t(5;10)(q33;q11.2) translocations associated with the TEL͞ PDGF␤R (2), TEL͞ABL (3), TEL͞JAK2 (4), and H4͞PDGF␤R (5, 6) fusions, respectively. Expression of these constitutively activated tyrosine kinases in a murine bone marrow transplantation assay system is both necessary and sufficient to cause a myeloproliferative disease in animals that has many of the features of CML in humans (7-9). The phenotype includes leukocytosis, splenomegaly, and extramedullary hematopoiesis with normal maturation and differentiation of myeloid lineage cells. Transformation is dependent on kinase activity, as demonstrated by point mutations that abrogate kinase activity, as well as by ABL and PDGF␤R kinase-specific inhibitors in vitro and in vivo (8,(10)(11)(12)(13)(14)(15).In contrast to chronic myeloid leukemias, cloning of recurrent chromosomal translocation breakpoints in acute leukemias has identified fusion genes that encode transcription factors or transcription regulatory proteins such as CBFB͞MYH11 (16), PML͞ RAR (17), MLL͞CBP (18), MLL͞ENL (19) or NUP98͞HOXA9 (20, 21). Expression of certain of th...